Novel substituted benzimidazole dosage forms and method of using same

ABSTRACT

Disclosed herein are methods kits, combinations, and compositions for treating gastric acid disorders employing pharmaceutical compositions comprising a proton pump inhibiting agent (PPI) and a buffering agent in a pharmaceutically acceptable carrier.

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/901,942, filed on Jul. 9, 2001, which is acontinuation-in-part of U.S. patent application Ser. No. 09/481,207,filed on Jan. 11, 2000, which is a continuation-in-part of U.S. patentapplication Ser. No. 09/183,422, filed on Oct. 30, 1998, now abandoned,which is a continuation-in-part of U.S. patent application Ser. No.08/680,376, filed on Jul. 15, 1996, now U.S. Pat. No. 5,840,737, whichclaims priority to U.S. Provisional Application Serial No. 60/009,608,filed on Jan. 4, 1996. This application claims priority to all suchprevious applications, and such applications are hereby incorporatedherein by reference.

TECHNICAL FIELD

[0002] The present invention relates to pharmaceutical preparationscomprising substituted benzimidazole proton pump inhibiting agents.

BACKGROUND OF THE INVENTION

[0003] Omeprazole is a substituted benzimidazole,5-methoxy-2-[(4-methoxy-3,5-dimethyl-2pyridinyl)methyl]sulfinyl]-1H-benzimidazole, that inhibits gastric acid secretion.Omeprazole belongs to a class of antisecretory compounds called protonpump inhibitors proton pump inhibiting agents (“TPIs”) that do notexhibit anti-cholinergic or H₂ histamine antagonist properties. Drugs ofthis class suppress gastric acid secretion by the specific inhibition ofthe H⁺, K⁺-ATPase enzyme system (proton pump) at the secretory surfaceof the gastric parietal cell.

[0004] Typically, omeprazole, lansoprazole and other proton pumpinhibitors are formulated in an enteric-coated solid dosage form (aseither a delayed-release capsule or tablet) or as an intravenoussolution (as a product for reconstitution), and are prescribed forshort-term treatment of active duodenal ulcers, gastric ulcers,gastroesophageal reflux disease (GERD), severe erosive esophagitis,poorly responsive symptomatic gastroesophageal reflux disease, andpathological hypersecretory conditions such as Zollinger Ellisonsyndrome. These conditions are caused by an imbalance between acid andpepsin production, called aggressive factors, and mucous, bicarbonate,and prostaglandin production, called defensive factors. Theseabove-listed conditions commonly arise in healthy or critically illpatients, and may be accompanied by significant upper gastrointestinalbleeding.

[0005] H₂-antagonists, antacids, and sucralfate are commonlyadministered to minimize the pain and the complications related to theseconditions. These drugs have certain disadvantages associated with theiruse. Some of these drugs are not completely effective in the treatmentof the aforementioned conditions and/or produce adverse side effects,such as mental confision, constipation, diarrhea, and thrombocytopenia.H₂-antagonists, such as ranitidine and cimetidine, are relatively costlymodes of therapy, particularly in NPO patients, which frequently requirethe use of automated infusion pumps for continuous intravenous infusionof the drug.

[0006] Patients with significant physiologic stress are at risk forstress-related gastric mucosal damage and subsequent uppergastrointestinal bleeding (Marrone and Silen, Pathogenesis, Diagnosisand Treatment of A cute Gastric Mucosa Lesions, CLIN GASTROENTEROL 13:635-650 (1984)). Risk factors that have been clearly associated with thedevelopment of stress-related mucosal damage are mechanical ventilation,coagulopathy, extensive burns, head injury, and organ transplant (Zinneret al., The Prevention of Gastrointestinal Tract Bleeding in Patients inan Intensive Care Unit, SURG. GYNECOL. OBSTET., 153: 214-220 (1981);Larson et al., Gastric Response to Severe Head Injury, AM. J. SURG. 147:97-105 (1984); Czaja et al., Acute Gastroduodenal Disease After ThermalInjury: An Endoscopic Evaluation of Incidence and Natural History, NENGL. J. MED, 291: 925-929 (1974); Skillman et al., Respiratory Failure,Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated withLethal Hemorrhage From Acute Stress Ulceration, AM. J. SURG., 117:523-530 (1969); and Cook et al., Risk Factors for GastrointestinalBleeding in Critically Ill Patients, N. ENGL. J. MED., 330:377-381(1994)). One or more of these factors are often found in critically ill,intensive care unit patients. A recent cohort study challenges otherrisk factors previously identified such as acid-base disorders, multipletrauma, significant hypertension, major surgery, multiple operativeprocedures, acute renal failure, sepsis, and coma (Cook et al., RiskFactors for Gastrointestinal Bleeding in Critically Ill Patients, N.ENGL. J. MED., 330:377-381 (1994)). Regardless of the risk type,stress-related mucosal damage results in significant morbidity andmortality. Clinically significant bleeding occurs in at least twentypercent of patients with one or more risk factors who are left untreated(Martin et al., Continuous Intravenous cimetidine DecreasesStress-related Upper Gastro-intestinal Hemorrhage Without PromotingPneumonia, CRIT. CARE MED., 21: 19-39 (1993)). Of those who bleed,approximately ten percent require surgery (usually gastrectomy) with areported mortality of thirty percent to fifty percent (Czaja et al.,Acute Gastroduodenal Disease After Thermal Injury: An EndoscopicEvaluation of Incidence and Natural History, N ENGL. J. MED, 291:925-929 (1974); Peura and Johnson, Cimetidine for Prevention andTreatment of Gastroduodenal Mucosal Lesions in Patients in an IntensiveCare Unit, ANN INTERN MED., 103: 173-177 (1985)). Those who do not needsurgery often require multiple transfusions and prolongedhospitalization. Prevention of stress-related upper gastrointestinalbleeding is an important clinical goal.

[0007] Omeprazole (Prilosec®), lansoprazole (Prevacid®) and other protonpump inhibitors reduce gastric acid production by inhibitingH⁺,K⁺-ATPase of the parietal cell—the final common pathway for gastricacid secretion (Fellenius et al., Substituted Benzimidazoles InhibitGastric Acid Secretion by Blocking H ⁺ ,K ⁺-ATPase, NATURE, 290:159-161(1981); Wallmark et al, The Relationship Between Gastric Acid Secretionand Gastric H ⁺ ,K ⁺-ATPase Activity, J. BIOL.CHEM., 260: 13681-13684(1985); Fryklund et al., Function and Structure of Parietal Cells AfterH ⁺ ,K ⁺-ATPase Blockade, AM. J. PHYSIOL., 254 (3 PT 1); G399-407(1988)).

[0008] Proton pump inhibitors contain a sulfinyl group in a bridgebetween substituted benzimidazole and pyridine rings, as illustratedbelow.

[0009] At neutral pH, omeprazole, lansoprazole and other proton pumpinhibitors are chemically stable, lipid-soluble, weak bases that aredevoid of inhibitory activity. These neutral weak bases reach parietalcells from the blood and diffuse into the secretory canaliculi, wherethe drugs become protonated and thereby trapped. The protonated agentrearranges to form a sulfenic acid and a sulfenamide. The sulfenamideinteracts covalently with sulfhydryl groups at critical sites in theextracellular (luminal) domain of the membrane-spanning H⁺,K⁺-ATPase(Hardman et al., Goodman & Gihnan's The Pharmacological Basis ofTherapeutics, p. 907 (9^(th) ed. 1996)). Omeprazole and lansoprazole,therefore, are prodrugs that must be activated to be effective. Thespecificity of the effects of proton pump inhibitors is also dependentupon: (a) the selective distribution of H⁺,K⁺-ATPase; (b) therequirement for acidic conditions to catalyze generation of the reactiveinhibitor; and (c) the trapping of the protonated drug and the cationicsulfenamide within the acidic canaliculi and adjacent to the targetenzyme. (Hardman et al., 1996).

[0010] Omeprazole and lansoprazole are available for oral administrationas enteric-coated granules in gelatin capsules. Other proton pumpinhibitors such as rabeprazole and pantoprazole are supplied asenteric-coated dosage forms. The enteric dosage forms of the prior arthave been employed because they are acid labile; thus, it is importantthat these drugs not be exposed to low pH gastric acid prior toabsorption. Although these drugs are stable at alkaline pH, they aredestroyed rapidly as pH falls (e.g., by gastric acid). Therefore, if themicro-encapsulation or the enteric coating is disrupted (e.g.,trituration to compound a liquid, or chewing the capsule), the dosageforms of the prior art will be exposed to degradation by the gastricacid in the stomach.

[0011] The absence of an intravenous or oral liquid dosage form in theUnited States has limited the testing and use of omeprazole,lansoprazole and rabeprazole in the critical care patient population.Barie et al., Therapeutic. Use of Omeprazole for RefractoryStress-induced Gastric Mucosal Hemorrhage, CRIT. CARE MED., 20:. 899-901(1992) have described the use of omeprazole enteric-coated pelletsadministered through a nasogastric tube to control gastrointestinalhemorrhage in a critical care patient with multi-organ failure. However,such pellets are not ideal as they can aggregate and occlude such tubes,and they are not suitable for patients who cannot swallow the pellets.AM J. HEALTH-SYST PHARM 56:2327-30 (1999).

[0012] Proton pump inhibitors such as omeprazole represent anadvantageous alternative to the use of H₂-antagonists, antacids, andsucralfate as a treatment for complications related to stress-relatedmucosal damage. However, in their current form (capsules containingenteric-coated granules or enteric-coated tablets), proton pumpinhibitors can be difficult or impossible to administer to patients whoare either unwilling or unable to swallow tablets or capsules, such ascritically ill patients, children, the elderly, and patients sufferingfrom dysphagia. Therefore, it would be desirable to formulate a protonpump inhibitor solution or suspension which can be enterally deliveredto a patient thereby providing the benefits of the proton pump inhibitorwithout the drawbacks of the current enteric-coated solid dosage forms.

[0013] Omeprazole, the first proton pump inhibitor introduced into use,has been formulated in many different embodiments such as in a mixtureof polyethylene glycols, adeps solidus and sodium lauryl sulfate in asoluble, basic amino acid to yield a formulation designed foradministration in the rectum as taught by U.S. Pat. No. 5,219,870 toKim.

[0014] U.S. Pat. No. 5,395,323 to Berglund ('323) discloses a device formixing a pharmaceutical from a solid supply into a parenterallyacceptable liquid form for parenteral administration to a patient. The'323 patent teaches the use of an omeprazole tablet which is placed inthe device and dissolved by normal saline, and infused parenterally intothe patient. This device and method of parenteral infusion of omeprazoledoes not provide the omeprazole solution as an enteral product, nor isthis omeprazole solution directly administered to the diseased oraffected areas, namely the stomach and upper gastrointestinal tract, nordoes this omeprazole formulation provide the immediate antacid effect ofthe present formulation.

[0015] U.S. Pat. No. 4,786,505 to Lovgren et al. discloses apharmaceutical preparation containing omeprazole together with analkaline reacting compound or an alkaline salt of omeprazole optionallytogether with an alkaline compound as a core material in a tabletformulation. The core is then enterically coated. The use of thealkaline material, which can be chosen from such substances as thesodium salt of carbonic acid, are used to form a “micro-pH” around eachomeprazole particle to protect the omeprazole which is highly sensitiveto acid pH. The powder mixture is then formulated into enteric-coatedsmall beads, pellets, tablets and may be loaded into capsules byconventional pharmaceutical procedures. This formulation of omeprazoledoes not teach a non-enteric-coated omeprazole dosage form which can beenterally administered to a patient who may be unable and/or unwillingto swallow capsules, tablets or pellets, nor does it teach a convenientform which can be used to make an omeprazole or other proton pumpinhibitor solution or suspension.

[0016] Several buffered omeprazole oral solutions/ suspensions have beendisclosed. For example, Pilbrant et al., Development ofan OralFormulation of Omeprazole, SCAND. J. GASTROENT. 20(Suppl. 108): 113-120(1985) teaches a suspension of micronized omeprazole, 60 mg, in 50 ml ofwater also containing 8 mmoles of sodium bicarbonate. The suspension wasadministered as follows: After fasting for at least 10 hours, patientswere given a solution of 8 mmoles of sodium bicarbonate in 50 ml ofwater. Five minutes later the patients took the omeprazole suspensionand rinsed it down with another 50 ml of sodium bicarbonate solution.Ten (10), 20 and 30 minutes later, a further 50 ml of sodium bicarbonatesolution was administered.

[0017] Andersson et el., Pharmacokinetics of Various Single Intravenousand Oral Doses of Omeprazole, EUR J. CLIN. PHARMACOL. 39: 195-197 (1990)discloses 10 mg, 40 mg, and 90 mg of oral omeprazole dissolved in PEG400, sodium bicarbonate and water. The concentration of omeprazolecannot be determined, as volumes of diluent are not disclosed.Nevertheless, it is apparent from this reference that multiple doses ofsodium bicarbonate were administered with and after the omeprazolesuspension.

[0018] Andersson et al., Pharmacokinetics and Bioavailability ofOmeprazole After Single and Repeated Oral Administration in HealthySubjects, BR. J. CLIN. PHARMAC. 29: 557-63 (1990) teaches the oral useof 20 mg of omeprazole, which was dissolved in 20 g of PEG 400 (sp.gravity=1.14) and diluted with 50 ml of water containing 8 mmoles ofsodium bicarbonate. In order to protect the omeprazole from gastricacid, the buffered solution was given with 48 mmoles of sodiumbicarbonate in 300 ml of water.

[0019] Regardh et al., The Pharmacokinetics of Omeprazole in Humans=AStudy of Single Intravenous and Oral Doses, THER. DRUG MON. 12: 163-72(1990) discloses an oral dose of omeprazole at a concentration 0.4 mg/mlafter the drug was dissolved in PEG 400, water and sodium bicarbonate (8mmoles). A solution containing 16 mmoles of sodium bicarbonate in 100 mlof water was concomitantly given with the omeprazole solution. That dosewas followed by a solution of 50 ml of 0.16 mol/L sodium bicarbonatethat was used for rinsing the vessel. In both the IV and oralexperiment, 50 ml of 0.16 mol/L sodium bicarbonate was administered 5minutes before administration, and 10, 20 and 30 minutes post-dose.

[0020] Landahl et al., Pharmacokinetics Study of Omeprazole in ElderlyHealthy Volunteers, CLIN. PHARMACOKINETICS 23 (6): 469-476 (1992)teaches the use of an oral dose of 40 mg of omeprazole dissolved in PEG400, sodium bicarbonate and water. This reference does not disclose thefinal concentrations utilized. Again, this reference teaches themultiple administration of sodium bicarbonate (8 mmol/L and 16 mmol/L)after the omeprazole solution.

[0021] Andersson et al., Pharmacokinetics of [ ¹⁴ C] Omeprazole inPatients with Liver Cirrhosis, CLIN. PHARMACOKINETICS 24(1): 71-78(1993) discloses the oral administration of 40 mg of omeprazole, whichwas dissolved in PEG 400, water and sodium bicarbonate. This referencedoes not teach the final concentration of the omeprazole solutionadministered, although it emphasizes the need for pre, concomitant andpost sodium bicarbonate dosing with a total of 48 mmoles to prevent aciddegradation of the drug.

[0022] Nakagawa, et al., Lansoprazole: Phase I Study of lansoprazole(AG-1749) Anti-ulcer Agent, J. CLIN. THERAPEUTICS & MED.(1991) teachesthe oral administration of 30 mg of lansoprazole suspended in 100 ml ofsodium bicarbonate, which was administered to patients through anasogastric tube.

[0023] All of the buffered omeprazole solutions described in thesereferences were administered orally, and were given to healthy subjectswho were able to ingest the oral dose. In all of these studies,omeprazole was suspended in a solution including sodium bicarbonate, asa pH buffer, in order to protect the acid sensitive omeprazole duringadministration. In all of these studies, repeated administration ofsodium bicarbonate both prior to, during, and following omeprazoleadministration were required in order to prevent acid degradation of theomeprazole given via the oral route of administration. In theabove-cited studies, as much as 48 mmoles of sodium bicarbonate in 300ml of water must be ingested for a single dose of omeprazole to beorally administered.

[0024] The buffered omeprazole solutions of the above cited prior artrequire the ingestion of large amounts of sodium bicarbonate and largevolumes of water by repeated administration. This has been considerednecessary to prevent acid degradation of the omeprazole. In theabove-cited studies, basically healthy volunteers, rather than sickpatients, were given dilute buffered omeprazole utilizing pre-dosing andpost-dosing with large volumes of sodium bicarbonate.

[0025] The administration of large amounts of sodium bicarbonate canproduce at least six significant adverse effects, which can dramaticallyreduce the efficacy of the omeprazole in patients and reduce the overallhealth of the patients. First, the fluid volumes of these dosingprotocols would not be suitable for sick or critically ill patients whomust receive multiple doses of omeprazole. The large volumes wouldresult in the distention of the stomach and increase the likelihood ofcomplications in critically ill patients such as the aspiration ofgastric contents.

[0026] Second, because bicarbonate is usually neutralized in the stomachor is absorbed, such that belching results, patients withgastroesophageal reflux may exacerbate or worsen their reflux disease asthe belching can cause upward movement of stomach acid (Brunton, Agentsfor the Control of Gastric Acidity and Treatment of Peptic Ulcers, IN,Goodman A G, et al. The Pharmacologic Basis of Therapeutics. (New York,p. 907 (1990)).

[0027] Third, patients with conditions such as hypertension or heartfailure are standardly advised to avoid the intake of excessive sodiumas it can cause aggravation or exacerbation of their hypertensiveconditions (Brunton, supra). The ingestion of large amounts of sodiumbicarbonate is inconsistent with this advice.

[0028] Fourth, patients with numerous conditions that typicallyaccompany critical illness should avoid the intake of excessive sodiumbicarbonate as it can cause metabolic alkalosis that can result in aserious worsening of the patient's condition.

[0029] Fifth, excessive antacid intake (such as sodium bicarbonate) canresult in drug interactions that produce serious adverse effects. Forexample, by altering gastric and urinary pH, antacids can alter rates ofdrug dissolution and absorption, bioavailability, and renal elimination(Brunton, supra).

[0030] Sixth, because the buffered omeprazole solutions of the prior artrequire prolonged administration of sodium bicarbonate, it makes itdifficult for patients to comply with the regimens of the prior art. Forexample, Pilbrant et al. disclose an oral omeprazole administrationprotocol calling for the administration to a subject who has beenfasting for at least ten hours, a solution of 8 mmoles of sodiumbicarbonate in 50 ml of water. Five minutes later, the subject ingests asuspension of 60 mg of omeprazole in 50 ml of water that also contains 8mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of8 mmoles sodium bicarbonate solution. Ten minutes after the ingestion ofthe omeprazole dose, the subject ingests 50 ml of bicarbonate solution(8 mmoles). This is repeated at twenty minutes and thirty minutes postomeprazole dosing to yield a total of 48 mmoles of sodium bicarbonateand 300 ml of water in total that are ingested by the subject for asingle omeprazole dose. Not only does this regimen require the ingestionof excessive amounts of bicarbonate and water, which is likely to bedangerous to some patients, it is unlikely that even healthy patientswould comply with this regimen.

[0031] It is well documented that patients who are required to followcomplex schedules for drug administration are non-compliant and, thus,the efficacy of the buffered omeprazole solutions of the prior art wouldbe expected to be reduced due to non-compliance. Compliance has beenfound to be markedly reduced when patients are required to deviate froma schedule of one or two (usually morning and night) doses of amedication per day. The use of the prior art buffered omeprazolesolutions which require administration protocols with numerous steps,different drugs (sodium bicarbonate+omeprazole+PEG 400 versus sodiumbicarbonate alone), and specific time allotments between each stage ofthe total omeprazole regimen in order to achieve efficacious results isclearly in contrast with both current drug compliance theories and humannature.

[0032] The prior art (Pilbrant et al., 1985) teaches that the bufferedomeprazole suspension can be stored at refrigerator temperatures for aweek and deep frozen for a year while still maintaining 99% of itsinitial potency. It would be desirable to have an omeprazole or otherproton pump inhibitor solution or suspension that could be stored atroom temperature or in a refrigerator for periods of time which exceedthose of the prior art while still maintaining 99% of the initialpotency. Additionally, it would be advantageous to have a form of theomeprazole and bicarbonate which can be utilized to instantly make theomeprazole solution/suspension of the present invention which issupplied in a solid form which imparts the advantages of improvedshelf-life at room temperature, lower cost to produce, less expensiveshipping costs, and which is less expensive to store.

[0033] It would, therefore, be desirable to have a proton pump inhibitorformulation, which provides a cost-effective means for the treatment ofthe aforementioned conditions without the adverse effect profile of H₂receptor antagonists, antacids, and sucralfate. Further, it would bedesirable to have a proton pump inhibitor formulation which isconvenient to prepare and administer to patients unable to ingest soliddosage forms such as tablets or capsules, which is rapidly absorbed, andcan be orally or enterally delivered as a liquid form or solid form. Itis desirable that the liquid formulation not clog indwelling tubes, suchas nasogastric tubes or other similar tubes, and which acts as anantacid immediately upon delivery.

[0034] It would further be advantageous to have a potentiator orenhancer of the pharmacological activity of the proton pump inhibitors.It has been theorized by applicant that the proton pump inhibitors canonly exert their effects on H⁺,K⁺-ATPase when the parietal cells areactive. Accordingly, applicant has identified, as discussed below,parietal cell activators that are administered to synergisticallyenhance the activity of the proton pump inhibitors.

[0035] Additionally, the intravenous dosage forms of proton pumpinhibitors of the prior art are often administered in larger doses thanthe oral forms. For example, the typical adult IV dose of omeprazole isgreater than 100 mg/day whereas the adult oral dose is 20 to 40 mg/day.Large IV doses are necessary to achieve the desired pharmacologic effectbecause, it is believed, many of the parietal cells are in a restingphase (mostly inactive) during an IV dose given to patients who are nottaking oral substances by mouth (npo) and, therefore, there is littleactive (that which is inserted into the secretory canalicular membrane)H⁺,K⁺-ATPase to inhibit. Because of the clear disparity in the amount ofdrug necessary for IV versus oral doses, it would be very advantageousto have compositions and methods for IV administration wheresignificantly less drug is required.

SUMMARY OF THE INVENTION AND ADVANTAGES

[0036] The foregoing advantages and objects are accomplished by thepresent invention. The present invention provides an oralsolution/suspension comprising a proton puMp inhibiting agent and atleast one buffering agent. The proton pump inhibiting agent can be anysubstituted benzimidazole compound having H⁺,K⁺-ATPase inhibitingactivity and being unstable to acid. The inventive composition canalternatively be formulated as a powder, tablet, suspension tablet,chewable tablet, capsule, two-part tablet or capsule, effervescentpowder, effervescent tablet, pellets and granules. Such dosage forms areadvantageously devoid of any enteric coating or delayed orsustained-release delivery mechanisms, and comprise a proton pumpinhibiting agent and at least one buffering agent to protect the protonpump inhibiting agent against acid degradation. Both the liquid and drydosage forms can further include anti-foaming agents, parietal cellactivators and flavoring agents.

[0037] In another embodiment, oral dosage forms are disclosed comprisinga combination of enteric-coated or delayed-released proton pumpinhibiting agent with an antacid(s). Such forms may optionally comprisea non-enteric-coated proton pump inhibiting agent.

[0038] Kits utilizing the inventive dry dosage forms are also disclosedherein to provide for the easy preparation of a liquid composition fromthe dry forms.

[0039] In accordance with the present invention, there is furtherprovided a method of treating gastric acid disorders by orallyadministering to a patient a pharmaceutical composition(s) and/or dosageform(s) disclosed herein.

[0040] Additionally, the present invention relates to a method forenhancing the pharmacological activity of an intravenously administeredproton pump inhibiting agent in which at least one parietal cellactivator is orally administered to the patient before, during and/orafter the intravenous administration of the proton pump inhibitingagent.

[0041] Finally, the present invention relates to a method for optimizingthe type and amount of buffer desirable for individual proton pumpinhibiting agents.

BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Other advantages of the present invention will be readilyappreciated as the same becomes better understood by reference to thefollowing detailed description when considered in connection with theaccompanying drawing wherein:

[0043]FIG. 1 is a graph showing the effect of the omeprazole solution ofthe present invention on gastric. pH in patients at risk for uppergastrointestinal bleeding from stress-related mucosal damage;

[0044]FIG. 2 is a flow chart illustrating a patient enrollment scheme;

[0045]FIG. 3 is a bar graph illustrating gastric pH both pre- andpost-administration of omeprazole solution according to the presentinvention;

[0046]FIG. 4 is a graph illustrating the stomach pH values after theoral administration of both ChocoBase plus lansoprazole and lansoprazolealone;

[0047]FIG. 5 is a graph illustrating a pH probe confirmation ofgastroesophageal reflux disease;

[0048]FIG. 6 is a graph illustrating an endoscopic confirmation ofgastroesophageal reflux disease;

[0049]FIG. 7 is a graph illustrating the percentage of patients who hadundergone any type of reflux therapy in the past;

[0050]FIG. 8 is a graph illustrating the effectiveness of the Choco-BaseFormulation 1; and

[0051]FIG. 9 is a graph illustrating the environmental pH values afteradministration of the proton pump inhibiting agent/buffer formulation.

DETAILED DESCRIPTION OF THE INVENTION

[0052] I. Introduction

[0053] The present invention is directed to methods, kits, combinations,and compositions for treating, preventing or reducing the risk ofdeveloping a gastrointestinal disorder or disease, or the symptomsassociated with, or related to a gastrointestinal disorder or disease ina subject in need thereof.

[0054] While the present invention may be embodied in many differentforms, several specific embodiments are discussed herein with theunderstanding that the present disclosure is to be considered only as anexemplification of the principles of the invention, and it is notintended to limit the invention to the embodiments illustrated. Forexample, where the present invention is illustrated herein withparticular reference to omeprazole, lansoprazole, pantoprazole,rabeprazole, esomeprazole, pariprazole, or leminoprazole, it will beunderstood that any other proton pump inhibiting agent, if desired, canbe substituted in whole or in part for omeprazole, lansoprazole,pantoprazole, rabeprazole, esomeprazole, pariprazole, or leminoprazolein the methods, kits, combinations, and compositions herein described.

[0055] The present invention provides a method of increasing absorptionof a proton pump inhibiting agent into the blood serum of a subject. Themethod comprises administering to the subject a solid pharmaceuticalcomposition comprising a proton pump inhibiting agent and a bufferingagent for oral administration and ingestion by the subject. Uponadministration the composition contacts the gastric fluid of the stomachand thereby increases the absorption of the proton pump inhibiting agentinto the blood serum greater than the absorption of the proton pumpinhibiting agent in the absence of the buffering agent. The amount ofbuffering agent present in the composition is sufficient to increase thegastric fluid pH of the stomach to a pH that prevents or inhibits aciddegradation of the proton pump inhibiting agent in the gastric fluid ofthe stomach, and to allow a measurable serum concentration of the protonpump inhibiting agent to be absorbed into the blood serum of thesubject. The concentration of the proton pump inhibiting agent can bedetermined using p harmacokinetic testing procedures known to thoseskilled in the art.

[0056] The present invention also provides for a method of treating agastrointestinal disorder in a subject in need thereof, by orallyadministering to the subject a solid pharmaceutical compositioncomprising a proton pump inhibiting agent and a buffering agent. Thebuffering agent is in an amount sufficient to increase the pH of thestomach content of the subject to a pH that prevents or inhibits aciddegradation of the proton pump inhibiting agent in the stomach and toallow blood serum absorption of the proton pump inhibiting agent greaterthan the blood serum absorption of the proton pump inhibiting agent inthe absence of the buffering agent when the composition is administeredorally to the subject. A therapeutically effective amount of proton pumpinhibiting agent is thus absorbed into the blood serum of the subject.

[0057] The present invention also provides a method of treating an acidrelated gastrointestinal disorder in a subject in need thereof, byorally administering to the subject a pharmaceutical composition in anoral dosage form for immediate release into an absorption pool of thesubject. In one embodiment of the present invention, the absorption poolis highly acidic pH. The composition comprises a proton pump inhibitingagent and a buffering agent. The buffering agent is in an amountsufficient to increase the pH of the absorption pool of the subject to apH that prevents or inhibits acid degradation of the proton pumpinhibiting agent and to allow absorption of the proton pump inhibitingagent from the absorption pool into blood serum of the subject greaterthan the absorption of the proton pump inhibiting agent in the absenceof the buffering agent when the composition is administered orally tothe subject. The amount of proton pump inhibiting agent is sufficient toachieve a measurable serum concentration of the proton pump inhibitingagent in the blood serum of the subject after oral administration of thecomposition.

[0058] The present invention also provides a method of making apharmaceutical composition for oral administration to a subject and forimmediate release of a proton pump inhibiting agent and a bufferingagent into an absorption pool of the subject. In one embodiment of thepresent invention the absorption pool is highly acidic pH. The methodcomprises admixing the proton pump inhibiting agent and the bufferingagent. The buffering agent is in an amount sufficient to increase the pHof the absorption pool of the subject to a pH that prevents or inhibitsacid degradation of the proton pump inhibiting agent in the absorptionpool and to allow absorption of the proton pump inhibiting agent fromthe absorption pool into blood serum of the subject greater than theabsorption of the proton pump inhibiting agent in the absence of thebuffering agent when the composition is administered orally to thesubject. The amount of the proton pump inhibiting agent is sufficient toachieve a measurable serum concentration in the blood serum of thesubject after oral administration of the composition.

[0059] In one embodiment of the present invention, the composition isadministered in an amount to achieve a measurable serum concentration ofthe proton pump inhibiting agent greater than about 0.1 μg/ml withinabout 15 minutes after administration of the composition.

[0060] In another embodiment of the present invention, the compositionis administered to the subject in an amount to achieve a measurableserum concentration of the proton pump inhibiting agent greater thanabout 0.1 μg/ml from about 15 minutes to about 6 hours afteradministration of the composition.

[0061] In yet another embodiment of the present invention, thecomposition is administered to the subject in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 0.15 μg/ml from about 15 minutes to about 1.5 hoursafter administration of the composition.

[0062] In still another embodiment of the present invention, thecomposition is administered to the subject in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 0.2 μg/ml within about 15 minutes afteradministration of the composition.

[0063] Besides being useful for human treatment, the present inventionis also useful for veterinary treatment of companion mammals, exoticanimals and farm animals, including mammals, rodents, and the like. Inone embodiment, the mammal includes a horse, dog, or cat.

[0064] For the purposes of this application, the term “proton pumpinhibitor,” or “PPI” or “proton pump inhibiting agent” means any agentpossessing pharmacological activity as an inhibitor of H⁺,K⁺-ATPase. Aclass of proton pump inhibiting agents useful in the methods, kits,combinations, and compositions of the present invention includessubstituted benzimidazole compounds possessing such pharmacologicalactivity as an inhibitor of H⁺,K⁺-ATPase. In one embodiment of thepresent invention, the proton pump inhibiting agent is acid sensitive.In another aspect of the invention, the substituted benzimidazolecompound employed in the methods, kits, combinations, and compositionscan include, for example, omeprazole, lansoprazole, pantoprazole,rabeprazole, esomeprazole, pariprazole, or leminoprazole. The definitionof “PPI,” or “proton pump inhibitor,” or “proton pump inhibiting agent”as used herein can also mean that the agent possessing pharmacologicalactivity as an inhibitor of H⁺,K⁺-ATPase may, if desired, be in the formof a salt, ester, amide, enantiomer, isomer, tautomer, prodrug,derivative or the like, provided the salt, ester, amide, enantiomer,isomer, tautomer, prodrug, or derivative is suitable pharmacologically,that is, effective in the present methods, combinations, kits, andcompositions. Substituted benzimidazole compounds and the salts, esters,amides, enantiomers, isomers, tautomers, prodrugs and derivativesthereof may be prepared using standard procedures known to those skilledin the art of synthetic organic chemistry and described, for example, byJ. March, Advanced Organic Chemistry Reactions, Mechanisms andStructure, 4th Ed. (New York: Wiley-Interscience, 1992).

[0065] As explained further herein, the proton pump inhibiting agentsgenerally inhibit ATPase in the same way. Differences in onset andrelative potencies are largely due to differences in the acidinstability of the parent compounds.

[0066] In one embodiment, the therapeutic agents of the presentinvention can be formulated as a single pharmaceutical composition or asindependent multiple pharmaceutical dosage forms. Pharmaceuticalcompositions according to the present invention include those suitablefor oral, rectal, buccal (for example, sublingual), or parenteral (forexample, intravenous) administration, although the most suitable routein any given case will depend on the nature and severity of thecondition being treated and on the nature of the particular compoundwhich is being used. Such dosage forms include, but are not limited to,a tablet, a powder, a suspension tablet, a chewable tablet, a capsule,an effervescent powder, an effervescent tablet, a pellet, or a granule.

[0067] In one embodiment of the present invention, the compositionscomprise a dry formulation, or a solution and/or a suspension of theproton pump inhibiting agent. As used herein, the terms “suspension” and“solution” are interchangeable with each other and generally mean asolution and/or suspension of the substituted benzimidazole in anaqueous medium. Such dry formulations, solutions and/or suspensions mayalso include, for example, a suspending agent (for example, gums,xanthans, cellulosics and sugars), a humectant (for example, sorbitol),a solubilizer (for example, ethanol, water, PEG and propylene glycol), asurfactant (for example, sodium lauryl sulfate, Spans, Tweens, and cetylpyridine), a preservative, an antioxidant (for example, parabens, andvitamins E and C), an anti-caking agent, a coating agent, a chelatingagent (for example, EDTA), a stabalizer, an antimicrobial agent, anantifungal or antibacterial agent (for example, parabens, chlorobutanol,phenol, sorbic acid), an isotonic agent (for example, sugar, sodiumchloride), a thickening agent (for example, methyl cellulose), aflavoring agent (for example, chocolate, thalmantin, aspartame, rootbeer or watermelon or other flavorings stable at pH 7 to 9), ananti-foaming agent (e.g., simethicone, Mylicon®), a disintegrant, a flowaid, a lubricant, an adjuvant, an excipient, a colorant, a diluent, amoistening agent, a preservative, a pharmaceutically compatible carrier,or a parietal cell activator.

[0068] In one embodiment, the present invention relates to apharmaceutical composition comprising a proton pump inhibiting agent, abuffering agent, and optionally a parietal cell activator. The protonpump inhibitor of the present invention may or may not be entericcoated, or sustained or delayed-release depending on the context inwhich the proton pump inhibiting agent in utilized. In one embodiment ofthe present invention the proton pump inhibiting agent is not entericcoated, or sustained or delayed-release. In yet another embodiment theproton pump inhibitor is enteric coated, or sustained ordelayed-release. And in another embodiment the composition may containboth an enteric coated proton pump inhibiting agent and a nonentericcoated proton pump inhibiting agent. Such a composition is contemplatedwhere both an immediate release of the proton pump inhibiting agent intothe absorption pool is desired as well as a delayed release of theproton pump inhibiting agent is desired providing an extendedtherapeutic effect.

[0069] In still another example, a pharmaceutical formulation isprepared by mixing enteric coated granules of a proton pump inhibitingagent with one or more buffering agents (e.g., omeprazole 20 mg granulesplus 500 mg sodium bicarbonate and 500 mg calcium carbonate) in a soliddosage form. Upon oral administration, the buffering agents elevate thegastric pH such that all or part of the enteric coating is dissolved inthe gastric fluid (rather than, for example, in the higher pHenvironment of the duodenum), and the omeprazole is available forimmediate release in the gastric fluid for absorption into thebloodstream. Many variations in this type of formulation (i.e., higheror lower amounts of inhibiting agent and/or buffering agent) may beutilized in the present invention.

[0070] After administration to the subject and absorption of the protonpump inhibiting agent (or administration intravenously), the agent isdelivered via the blood serum to various tissues and cells of the bodyincluding the parietal cells. Not intending to be bound by any onetheory, research suggests that when the proton pump inhibiting agent isin the form of a weak base and is non-ionized, it freely passes throughphysiologic membranes, including the cellular membranes of the parietalcell. It is believed that the non-ionized proton pump inhibiting agentmoves into the acid-secreting portion of the parietal cell, thesecretory canaliculus. Once in the acidic milieu of the secretorycanaliculus, the proton pump inhibiting agent is apparently protonated(ionized) and converted to the active form of the drug. Generally,ionized proton pump inhibiting agents are membrane impermeable and formdisulfide covalent bonds with cysteine residues in the alpha subunit ofthe proton pump. Such active forms are included within the definition of“PPI,” “proton pump inhibitor,” or “proton pump inhibiting agent”herein.

[0071] The proton pump inhibiting agent is administered and dosed inaccordance with good medical practice, taking into account the clinicalcondition of the individual patient, the site and method ofadministration, scheduling of administration, and other factors known tomedical practitioners.

[0072] For the purposes of this application, the term “buffering agent”or “buffer” means any pharmaceutically appropriate weak base or strongbase (and mixtures thereof) that, when formulated or delivered With(e.g., before, during and/or after) the proton pump inhibiting agent,functions to substantially prevent or inhibit the acid degradation ofthe proton pump inhibiting agent by gastric acid sufficient to preservethe bioavailability of the proton pump inhibiting agent administered. Abuffering agent useful in the methods, kits, combinations, andcompositions of the present invention include a bicarbonate salt ofGroup IA metal, such as, for example, magnesium hydroxide, magnesiumlactate, magnesium gluconate, magnesium oxide, magnesium carbonate, ormagnesium silicate. Other buffering agents include, but are not limitedto, potassium bicarbonate, magnesium hydroxide, magnesium lactate,magnesium gluconate, other magnesium salts, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate coprecipitate, a mixture of an amino acidand a buffer, a mixture of aluminum glycinate and a buffer, a mixture ofan acid salt of an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Other buffering agents that may beused in the methods, kits, combinations, and compositions of the presentinvention include, but are not limited to, sodium citrate, sodiumtartarate, sodium acetate, sodium carbonate, sodium polyphosphate,potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate,disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodiumphosphate, tripotassium phosphate, sodium acetate, potassiummetaphosphate, magnesium oxide, magnesium hydroxide, magnesiumcarbonate, magnesium silicate, calcium acetate, calciumglycerophosphate, calcium cholride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, and other calcium salts.Mixtures of any of the foregoing can also be used in the methods, kits,combinations, and compositions of the present invention.

[0073] The buffering agent is administered in an amount sufficient tosubstantially prevent or inhibit the acid degradation of the proton pumpinhibiting agent by gastric acid sufficient to preserve thebioavailability of the proton pump inhibiting agent administered, andpreserve the ability of the proton pump inhibiting agent to elicit atherapeutic effect. Therefore, the buffering agent of the presentinvention, when in the presence of the biological fluids of the stomach,must only elevate the pH of these biological fluids sufficiently toachieve adequate bioavailability of the drug to effect therapeuticaction.

[0074] In one embodiment, the buffering agent is present in the methods,kits, combinations, and compositions of the present invention in anamount of about 0.05. mEq to about 5.0 mEq per mg of proton pumpinhibiting agent. In another embodiment of the present invention thebuffering agent is present in an amount of about 0.1 mEq to about 2.5mEq per mg of proton pump inhibiting agent. In yet another embodiment ofthe present invention the buffering agent is present in an amount of atleast 10 mEq. In yet another embodiment of the present invention thebuffering agent is present in an amount of about 10 mEq to about 70 mEq.In still another embodiment, the buffering agent is present in an amountof about 20 mEq to about 40 mEq. And in yet another embodiment of thepresent invention, the amount of the buffering agent is present in anamount more than about 20 times the amount of the proton pump inhibitingagent on a weight to weight basis in the composition.

[0075] In one embodiment of the present invention, the buffering agentis sodium bicarbonate and is present in the methods, kits, combinationsand compositions in an amount of at least 250 mg. In another embodiment,the sodium bicarbonate is present in an amount of at least 800 mg. Inyet another embodiment, the sodium bicarbonate is present in an amountfrom about 250 mg to about 4000 mg. And in still another embodiment, thesodium bicarbonate is present in an amount from about 1000 mg to about1680 mg.

[0076] In one embodiment of the present invention, the buffering agentis calcium carbonate and is present in the methods, kits, combinationsand compositions in an amount of at least 250 mg. In another embodiment,the calcium carbonate is present in an amount of at least 800 mg. In yetanother embodiment, the calcium carbonate is present in an amount fromabout 250 mg to about 4000 mg. And in still another embodiment, thecalcium carbonate is present in an amount from about 500 mg to about1000 mg.

[0077] The term “effective amount” means, consistent with considerationsknown in the art, the amount of proton pump inhibiting agent or otheragent effective to elicit a pharmacologic effect or therapeutic effect(including, but not limited to, raising of gastric pH, reducinggastrointestinal bleeding, reducing in the need for blood transfusion,improving survival rate, more rapid recovery, parietal cell activationand H⁺,K⁺-ATPase inhibition or improvement or elimination of symptoms,and other indicators as are selected as appropriate measures by thoseskilled in the art), without undue adverse side effects.

[0078] The term “measurable serum concentration” means the serumconcentration (typically measured in mg, μg, or ng of therapeutic agentper ml, dl, or l of blood serum) of a therapeutic agent absorbed intothe bloodstream after administration. Illustratively, the serumconcentration of a proton pump inhibiting agent of the present inventionthat corresponds to a measurable serum concentration for an adultsubject is greater than about 5 ng/ml. In another embodiment of thepresent invention, the serum concentration of the proton pump inhibitingagent that corresponds to a measurable serum concentration for an adulthuman is less than about 10.0 μg/ml. In yet another embodiment of thepresent invention, the serum concentration of the proton pump inhibitingagent that corresponds to a measurable serum concentration for an adulthuman is from about 0.01 μg/ml to about 5 μg/ml. And in still anotherembodiment of the present invention, the serum concentration of theproton pump inhibiting agent that corresponds to a measurable serumconcentration for an adult human is from about 0.25 μg/ml to about 2.5μg/ml.

[0079] In one embodiment of the present invention, the composition isadministered to a subject in a therapeutically-effective amount, thatis, the composition is administered in an amount that achieves atherapeutically-effective dose of a proton pump inhibiting agent in theblood serum of a subject for a period of time to elicit a desiredtherapeutic effect. Illustratively, in a fasting adult human (fastingfor generally at least 10 hours) the composition is administered toachieve a therapeutically-effective dose of a proton pump inhibitingagent in the blood serum of a subject from about 5 minutes afteradministration of the composition. In another embodiment of the presentinvention, a therapeutically-effective dose of the proton pumpinhibiting agent is achieved in the blood serum of a subject at about 10minutes from the time of administration of the composition to thesubject. In another embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 20 minutes from thetime of administration of the composition to the subject. In yet anotherembodiment of the present invention, a therapeutically-effective dose ofthe proton pump inhibiting agent is achieved in the blood serum of asubject at about 30 minutes from the time of administration of thecomposition to the subject. In still another embodiment of the presentinvention, a therapeutically-effective dose of the proton pumpinhibiting agent is achieved in the blood serum of a subject at about 40minutes from the time of administration of the composition to thesubject. In one embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 20 minutes to about 12hours from the time of administration of the composition to the subject.In another embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 20 minutes to about 6hours from the time of administration of the composition to the subject.In yet another embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 20 minutes to about 2hours from the time of administration of the composition to the subject.In still another embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 40 minutes to about 2hours from the time of administration of the composition to the subject.And in yet another embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 40 minutes to about 1hour from the time of administration of the composition to the subject.

[0080] In general, a composition of the present invention isadministered at a dose suitable to provide an average blood serumconcentration of a proton pump inhibiting agent of at least about 1.0μg/ml in a subject over a period of about 1 hour after administration.Contemplated compositions of the present invention provide a therapeuticeffect as proton pump inhibiting agent medications over an interval ofabout 5 minutes to about 24 hours after administration, enablingonce-a-day or twice-a-day administration if desired. In one embodimentof the present invention, the composition is administered at a dosesuitable to provide an average blood serum concentration of a protonpump inhibiting agent of at least about 1.0 μg/ml in a subject about 10,20, 30, or 40 minutes after administration of the composition to thesubject.

[0081] The amount of therapeutic agent necessary to elicit a therapeuticeffect can be experimentally determined based on, for example, theabsorption rate of the agent into the blood serum, the bioavailabilityof the agent, and the amount of protein binding of the agent. It isunderstood, however, that specific dose levels of the therapeutic agentsof the present invention for any particular patient depends upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, and diet of thesubject (including, for example, whether the subject is in a fasting orfed state), the time of administration, the rate of excretion, the drugcombination, and the severity of the particular disorder being treatedand form of administration. Treatment dosages generally may be titratedto optimize safety and efficacy. Typically, dosage-effect relationshipsfrom in vitro and/or in vivo tests initially can provide useful guidanceon the proper doses for subject administration. Studies in animal modelsgenerally may be used for guidance regarding effective dosages fortreatment of gastrointestinal disorders or diseases in accordance withthe present invention. In terms of treatment protocols, it should beappreciated that the dosage to be administered will depend on severalfactors, including the particular agent that is administered, the routeadministered, the condition of the particular subject, etc. Generallyspeaking, one will desire to administer an amount of the compound thatis effective to achieve a serum level commensurate with theconcentrations found to be effective in vitro for a period of timeeffective to elicit a therapeutic effect. Thus, where a compound isfound to demonstrate in vitro activity at, for example, 10 ng/ml, onewill desire to administer an amount of the drug that is effective toprovide at least about a 10 ng/ml concentration in vivo for a period oftime that elicits a desired therapeutic effect, for example, raising ofgastric pH, reducing gastrointestinal bleeding, reducing the need forblood transfusion, improving survival rate, more rapid recovery,parietal cell activation and H⁺,K⁺-ATPase inhibition or improvement orelimination of symptoms, and other indicators as are selected asappropriate measures by those skilled in the art. Determination of theseparameters is well within the skill of the art. These considerations arewell known in the art and are described in standard textbooks.

[0082] In order to measure and determine the gastrointestinal disorder-or disease-effective amount of a proton pump inhibiting agent to bedelivered to a subject, serum proton pump inhibiting agentconcentrations can be measured using standard assay techniques.

[0083] “Therapeutic window” refers to the range of plasmaconcentrations, or the range of levels of therapeutically activesubstance at the site of action, with a high probability of eliciting atherapeutic effect.

[0084] It will be understood that a therapeutically effective amount ofa proton pump inhibiting agent and/or a buffering agent that isadministered to a subject is dependent inter alia on the body weight ofthe subject. Illustratively, where the agent is a substitutedbenzimidazole such as, for example, omeprazole, lansoprazole,pantoprazole, rabeprazole, esomeprazole, pariprazole, or leminoprazole,and the subject is a child or a small animal (e.g., a dog), for example,a relatively low amount of the agent in the dose range of about 1 mg toabout 20 mg is likely to provide blood serum concentrations consistentwith therapeutic effectiveness. Where the subject is an adult human or alarge animal (e.g., a horse), achievement of such blood serumconcentrations of the agent are likely to require dose units containinga relatively greater amount of the agent. For example, in an adult humanthe methods, kits, combinations, and compositions of the presentinvention comprise a proton pump inhibiting agent, for example,omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole,pariprazole, or leminoprazole, in a dosage amount of about 5 mg to about1000 mg, or of about 7.5 mg to about 300 mg, or of about 10 mg to about100 mg, or of about 15 mg to about 80 mg.

[0085] The solid compositions of the present invention are generally inthe form of discrete unit dose articles, such as in a tablet, powder,suspension tablet, chewable tablet, capsule, effervescent powder,effervescent tablet, pellet, or granule. Such unit dose articlestypically contain about 1 mg to about 1000 mg of the proton pumpinhibiting agent, or about 5 mg to about 300 mg, or about 10 mg to about100 mg, or about 15 mg to about 80 mg. Illustratively, these unit dosearticles may contain a 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg,50 mg, 60 mg, 75 mg, 80 mg, or 100 mg dose of a proton pump inhibitingagent. In one embodiment, the buffering agent is present in compositionsof the present invention in an amount of about 0.05 mEq to about 5.0 mEqper mg of proton pump inhibiting agent, or about 0.1 mEq to about 2.5mEq per mg of proton pump inhibiting agent, or about 0.5 mEq to about1.0 mEq per mg of proton pump inhibiting agent. Such dosage units may begiven at least once or twice a day, or as many times as needed to elicita therapeutic response. A particular unit dosage form can be selected toaccommodate the desired frequency of administration used to achieve aspecified daily dosage.

[0086] A pharmaceutical formulation of the proton pump inhibiting agentsutilized in the present invention can be administered orally orenterally to the subject. This can be accomplished, for example, byadministering the solution via a nasogastric (ng) tube or otherindwelling tubes placed in the GI tract. In one embodiment of thepresent invention, in order to avoid the critical disadvantagesassociated with administering large amounts of sodium bicarbonate, theproton pump inhibiting agent solution of the present invention isadministered in a single dose which does not require any furtheradministration of bicarbonate, or other buffer following theadministration of the proton pump inhibiting agent solution, nor does itrequire a large amount of bicarbonate or buffer in total. That is,unlike the prior art proton pump inhibiting agent solutions andadministration protocols outlined above, the formulation of the presentinvention is given in a single dose, which does not requireadministration of bicarbonate either before or after administration ofthe proton pump inhibiting agent. The present invention eliminates theneed to pre-or post-dose with additional volumes of water and sodiumbicarbonate. The amount of bicarbonate administered via the single doseadministration of the present invention is less than the amount ofbicarbonate administered as taught in the prior art references citedabove.

[0087] The term “immediate release” is intended to refer to any protonpump inhibiting agent containing formulation in which release of theproton pump inhibiting agent is immediate, i.e., with an “immediaterelease” formulation, oral administration results in immediate releaseof the proton pump inhibiting agent into an absorption pool. See also,Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton,Pa.: Mack Publishing Company, 1995). As discussed herein, immediate andnonimmediate release (or controlled release) can be defined kineticallyby reference to the following equation:

[0088] The absorption pool represents a solution of the drugadministered at a particular absorption site, and K_(r), K_(a), andK_(e) are first-order rate constants for (1) release of the drug fromthe formulation, (2) absorption, and (3) elimination, respectively. Forimmediate release dosage forms, the rate constant for drug releaseK_(r), is generally equal to or greater than the absorption rateconstant K_(a). For controlled release formulations, the opposite isgenerally true, i.e., K_(r), <<K_(a), such that the rate of release ofdrug from the dosage form is the rate-limiting step in the delivery ofthe drug to the target area. The term “controlled release” includes anynonimmediate release formulation, including but not limited to entericcoated formulations and sustained release, delayed release and pulsatilerelease formulations. The term “sustained release” is used in itsconventional sense to refer to a drug formulation that provides forgradual release of a drug over an extended period of time, and, maysometimes, although not necessarily, result in substantially constantblood levels of a drug over an extended time period.

[0089] “Plasma concentration” refers to the concentration of a substancein blood plasma or blood serum.

[0090] “Drug absorption” or “absorption” refers to the process ofmovement from the site of administration of a drug toward the systemiccirculation.

[0091] “Bioavailability” refers to the extent to which an active moiety(drug or metabolite) is absorbed into the general circulation andbecomes available at the site of drug action in the body.

[0092] “Drug elimination” or “elimination” refers to the sum of theprocesses of drug loss from the body.

[0093] “Metabolism” refers to the process of chemical alteration ofdrugs in the body.

[0094] “Pharmacodynamics” refers to the factors which determine thebiologic response observed relative to the concentration of drug at asite of action.

[0095] “Pharmacokinetics” refers to the factors which determine theattainment and maintenance of the appropriate concentration of drug at asite of action.

[0096] “Half-life” refers to the time required for the plasma drugconcentration or the amount in the body to decrease by 50% from itsmaximum concentration.

[0097] The use of the term “highly acidic pH” in the present disclosuremeans a pH in the range of about 1 to 4. The use of the term “lessacidic to basic pH” in the present disclosure means a pH greater thanabout 4 up to approximately about 8.0.

[0098] The use of the term “about” in the present disclosure means“approximately,” and illustratively, the use of the term “about”indicates that dosages slightly outside the cited ranges may also beeffective and safe, and such dosages are also encompassed by the scopeof the present claims.

[0099] The phrase “pharmaceutically acceptable” is used adjectivallyherein to mean that the modified noun is appropriate for use in apharmaceutical product. Pharmaceutically acceptable cations includemetallic ions and organic ions. More preferred metallic ions include,but are not limited, to appropriate alkali metal salts, alkaline earthmetal salts and other physiological acceptable metal ions. Exemplaryions include aluminum, calcium, lithium, magnesium, potassium, sodiumand zinc in their usual valences. Preferred organic ions includeprotonated tertiary amines and quaternary ammonium cations, including inpart, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Exemplary pharmaceutically acceptableacids include without limitation hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid,formic acid, tartaric acid, maleic acid, malic acid, citric acid,isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronicacid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid,aspartic acid, glutamic acid, benzoic acid, and the like.

[0100] The phrase “gastrointestinal disorder” or “gastrointestinaldisease” refers generally to a disorder or disease that occurs in amammal due an imbalance between acid and pepsin production, calledaggressive factors, and mucous, bicarbonate, and prostaglandinproduction, called defensive factors. In mammals, such disorders ordiseases include, but are not limited to, duodenal ulcer, gastric ulcer,acid dyspepsia, gastroesophageal reflux disease (GERD), severe erosiveesophagitis, poorly responsive symptomatic gastroesophageal refluxdisease, heartburn, other esophageal disorders, and a gastrointestinalpathological hypersecretory condition such as Zollinger EllisonSyndrome. Treatment of these conditions is accomplished by administeringto a subject a therapeutically effective amount of a pharmaceuticalcomposition according to the present invention.

[0101] The term “treat” or “treatment” as used herein refers to anytreatment of a disorder or disease associated with gastrointestinaldisorder, and includes, but is not limited to, preventing the disorderor disease from occurring in a mammal which may be predisposed to thedisorder or disease, but has not yet been diagnosed as having thedisorder or disease; inhibiting the disorder or disease, for example,arresting the development of the disorder or disease; relieving thedisorder or disease, for example, causing regression of the disorder ordisease; or relieving the condition caused by the disease or disorder,for example, stopping the symptoms of the disease or disorder.

[0102] The term “prevent” or “prevention,” in relation to agastrointestinal disorder or disease, means no gastrointestinal disorderor disease development if none had occurred, or no furthergastrointestinal disorder or disease development if there had alreadybeen development of the gastrointestinal disorder or disease.

[0103] The present invention also relates to administration kits to easemixing and administration. Illustratively, a month's supply of powder ortablets, for example, can be packaged with a separate month's supply ofdiluent, and a re-usable plastic dosing cup. More specifically, thepackage could contain thirty (30) suspension tablets containing 20 mgomeprazole each, 1 L sodium bicarbonate 8.4% solution, and a 30 ml dosecup. The user places the tablet in the empty dose cup, fills it to the30 ml mark with the sodium bicarbonate, waits for it to dissolve (gentlestirring or agitation may be used), and then ingests the suspension. Oneskilled in the art will appreciate that such kits may contain manydifferent variations of the above components. For example, if thetablets or powder are compounded to contain proton pump inhibiting agentand buffering agent, the diluent may be water, sodium bicarbonate, orother compatible diluent, and the dose cup can be larger or smaller than30 ml in size. Also, such kits can be packaged in unit dose form, or asweekly, monthly, or yearly kits, etc.

[0104] In human therapy, it is important to provide a dosage form thatdelivers the required therapeutic amount of the drug in vivo, andrenders the drug bioavailable in a rapid manner. The formulations of thepresent invention satisfy these needs.

[0105] II. Preparation of Oral Liquids

[0106] As described in Phillips U.S. Pat. No. 5,840,737, the liquid oralpharmaceutical composition of the present invention is prepared bymixing omeprazole enteric-coated granules (Prilosec® AstraZeneca), oromeprazole base, or other proton pump inhibitor or derivatives thereofwith a solution including at least one buffering agent (with or withouta parietal cell activator, as discussed below). In one embodiment,omeprazole or other proton pump inhibitor, which can be obtained frompowder, capsules, and tablets or obtained from the solution forparenteral administration, is mixed with a sodium bicarbonate solutionto achieve a desired final omeprazole (or other proton pump inhibitor)concentration. As an example, the concentration of omeprazole in thesolution can range from approximately 0.4 mg/ml to approximately 10.0mg/ml. The preferred concentration for the omeprazole in the solutionranges from approximately 1.0 mg/ml to approximately 4.0 mg/ml, with 2.0mg/ml being the standard concentration. For lansoprazole (Prevacid® TAPPharmaceuticals, Inc.) the concentration can range from about 0.3 mg/mlto 10 mg/ml with the preferred concentration being about 3 mg/ml.

[0107] The pharmaceutically acceptable carrier of the oral liquid maycomprise a bicarbonate salt of Group IA metal as buffering agent, andcan be prepared by mixing the bicarbonate salt of the Group IA metal,preferably sodium bicarbonate, with water. The concentration of thebicarbonate salt of the Group IA metal in the composition generallyranges from approximately 5.0 percent to approximately 60.0 percent. Inone embodiment, the content of the bicarbonate salt of the Group IAmetal ranges from about 3 mEq to about 45 mEq per oral dose.

[0108] In another embodiment, the amount of sodium bicarbonate 8.4% usedin the solution of the present invention is approximately 1 mEq (ormmole) sodium bicarbonate per 2 mg omeprazole, with a range ofapproximately 0.2 mEq (mmole) to 5 mEq (mmole) per 2 mg of omeprazole.

[0109] In an embodiment of the present invention, enterically-coatedomeprazole particles are obtained from delayed release capsules(Prilosec® AstraZeneca). Alternatively, omeprazole base powder can beused. The enterically coated omeprazole particles are mixed with asodium bicarbonate (NaHCO₃) solution (8.4%), which dissolves the entericcoating and forms an omeprazole solution.

[0110] The inventive solutions and other dosage forms of the presentinvention have pharmacokinetic advantages over standard enteric-coatedand time-released proton pump inhibitor dosage forms, including: (a)more rapid drug absorbance time (about 10 to 60 minutes) followingadministration for the proton pump inhibitor solution or dry form versusabout 1 to 3 hours following administration for the enteric-coatedpellets; (b) the buffer solution protects the proton pump inhibitor fromacid degradation prior to absorption; (c) the buffer acts as an antacidwhile the proton pump inhibitor is being absorbed for rapid antacidrelief; and (d) the solutions can be administered through an existingindwelling tube without clogging, for example, nasogastric or otherfeeding tubes (jejunal or duodenal), including small bore needlecatheter feeding tubes.

[0111] Solutions, suspensions and powders for reconstitutable deliverysystems include vehicles such as suspending agents (for example, gums,xanthans, celluloses and sugars), humectants (for example, sorbitol),solubilizers (for example, ethanol, water, PEG and propylene glycol),surfactants (for example, sodium lauryl sulfate, Spans, Tweens, andcetyl pyridine), preservatives and antioxidants (for example, parabens,vitamins E and C, and ascorbic acid), anti-caking agents, coatingagents, and chelating agents (for example, EDTA).

[0112] Additionally, various additives can be incorporated into theinventive solution to enhance its stability, sterility and isotonicity.Antimicrobial preservatives, such as ambicin, antioxidants, chelatingagents, and additional buffers can be added. However, microbiologicalevidence shows that this formulation inherently possesses antimicrobialand antifungal activity. Various antibacterial and antifungal agentssuch as, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like can enhance prevention of the action of microorganisms.

[0113] In many cases, it would be desirable to include isotonic agents,for example, sugars, sodium chloride, and the like. Additionally,thickening agents such as methyl cellulose are desirable to use in orderto reduce the settling of the omeprazole or other proton pump inhibitoror derivatives thereof from the suspension.

[0114] The liquid oral solution may further comprise flavoring agents(e.g., chocolate, thalmantin, aspartame, root beer or watermelon) orother flavorings stable at pH 7 to 9, anti-foaming agents (e.g.,simethicone 80 mg, Mylicon®) and parietal cell activators (discussedbelow).

[0115] The present invention further includes a pharmaceuticalcomposition comprising omeprazole or other proton pump inhibitor andderivatives thereof and at least one buffering agent in a formconvenient for storage, whereby when the composition is placed into anaqueous solution, the composition dissolves and/or disperses yielding asuspension suitable for enteral administration to a subject. Thepharmaceutical composition is in a solid form prior to dissolution orsuspension in an aqueous solution. The omeprazole or other proton pumpinhibiting agents and buffering agent can be formed into a tablet,capsule, pellets or granules, by methods well known to those skilled inthe art.

[0116] The resultant omeprazole solution is stable at room temperaturefor several weeks and inhibits the growth of bacteria or fungi as shownin Example X below. Indeed, as established in Example XIII, the solutionmaintains greater than 90% of its potency for 12 months. By providing apharmaceutical composition including omeprazole or other proton pumpinhibitor with buffer in a solid form, which can be later dissolved orsuspended in a prescribed amount of aqueous solution to yield thedesired concentration of omeprazole and buffer, the cost of production,shipping, and storage are greatly reduced as no liquids are shipped(reducing weight and cost), and there is no need to refrigerate thesolid form of the composition or the solution. Once mixed the resultantsolution can then be used to provide dosages for a single subject over acourse of time, or for several subjects.

[0117] III. Tablets and Other Solid Dosage Forms

[0118] As mentioned above, and as described in part in Phillips U.S.Pat. No. 5,840,737, the formulations of the present invention can alsobe manufactured in concentrated forms, such as powders, capsules,tablets, suspension tablets and effervescent tablets or powders, whichcan be swallowed whole or first dissolved such that upon reaction withwater, gastric secretions or other diluent, the aqueous form of thepresent invention is produced.

[0119] The present pharmaceutical tablets or other solid dosage formsdisintegrate rapidly in aqueous media and form an aqueous solution ofthe proton pump inhibitor and buffering agent with minimal shaking oragitation. Such tablets utilize commonly available materials and achievethese and other desirable objectives. The tablets or other solid dosageforms of this invention provide for precise dosing of a proton pumpinhibitor that may be of low solubility in water. They may beparticularly useful for medicating children and the elderly and othersin a way that is much more acceptable than swallowing or chewing atablet. The tablets that are produced have low friability, making themeasily transportable.

[0120] The term “suspension tablets” as used herein refers to compressedtablets which rapidly disintegrate after they are placed in water, andare readily dispersible to form a suspension containing a precise dosageof the proton pump inhibitor. The suspension tablets of this inventioncomprise, in combination, a therapeutic amount of a proton pumpinhibitor, a buffering agent, and a disintegrant. More particularly, thesuspension tablets comprise about 20 mg omeprazole and about 4-30 mEq ofsodium bicarbonate.

[0121] Croscarmellose sodium is a known disintegrant for tabletformulations, and is available from FMC Corporation, Philadelphia, Pa.under the trademark Ac-Di-Sol®. It is frequently blended in compressedtableting formulations either alone or in combination withmicrocrystalline cellulose to achieve rapid disintegration of thetablet.

[0122] Microcrystalline cellulose, alone or co processed with otheringredients, is also a common additive for compressed tablets and iswell known for its ability to improve compressibility of difficult tocompress tablet materials. It is commercially available under theAvicel® trademark. Two different Avicel® products are utilized, Avicel®PH which is microcrystalline cellulose, and Avicel® AC-815, a coprocessed spray dried residue of microcrystalline cellulose and acalcium-sodium alginate complex in which the calcium to sodium ratio isin the range of about 0.40:1 to about 2.5:1. While AC-815 is comprisedof 85% microcrystalline cellulose (MCC) and 15% of a calcium-sodiumalginate complex, for purposes of the present invention this ratio maybe varied from about 75% MCC to 25% alginate up to about 95% MCC to 5%alginate. Depending on the particular formulation and active ingredient,these two components may be present in approximately equal amounts or inunequal amounts, and either may comprise from about 10% to about 50% byweight of the tablet.

[0123] The suspension tablet composition may, in addition to theingredients described above, contain other ingredients often used inpharmaceutical tablets, including flavoring agents, sweetening agents,flow aids, lubricants or other common tablet adjuvants, as will beapparent to those skilled in the art. Other disintegrants, such ascrospovidone and sodium starch glycolate may be employed, althoughcroscarmellose sodium is preferred.

[0124] In addition to the suspension tablet, the solid formulation ofthe present invention can be in the form of a powder, a tablet, acapsule, or other suitable solid dosage form (e.g., a pelleted form oran effervescing tablet, troche or powder), which creates the inventivesolution in the presence of diluent or upon ingestion. For example, thewater in the stomach secretions or water, which is used to swallow thesolid dosage form, can serve as the aqueous diluent.

[0125] Compressed tablets are solid dosage forms prepared by compactinga formulation containing an active ingredient and excipients selected toaid the processing and improve the properties of the product. The term“compressed tablet” generally refers to a plain, uncoated tablet fororal ingestion, prepared by a single compression or by pre-compactiontapping followed by a final compression.

[0126] Dry oral formulations can contain excipients such as binders (forexample, hydroxypropylmethylcellulose, polyvinyl pyrilodone, othercellulosic materials and starch), diluents (for example, lactose andother sugars, starch, dicalcium phosphate and cellulosic materials),disintegrating agents (for example, starch polymers and cellulosicmaterials) and lubricating agents (for example, stearates and talc).

[0127] Such solid forms can be manufactured as is well known in the art.Tablet forms can include, for example, one or more of lactose, mannitol,corn starch, potato starch, microcrystalline cellulose, acacia, gelatin,colloidal silicon dioxide, croscarmellose sodium, talc, magnesiumstearate, stearic acid, and other excipients, colorants, diluents,buffering agents, moistening agents, preservatives, flavoring agents,and pharmaceutically compatible carriers. The manufacturing processesmay employ one, or a combination of, four established methods: (1) drymixing; (2) direct compression; (3) milling; and (4) non-aqueousgranulation. Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Such tablets may also comprise film coatings, whichpreferably dissolve upon oral ingestion or upon contact with diluent.

[0128] Non-limiting examples of buffering agents which could be utilizedin such tablets include sodium bicarbonate, alkali earth metal saltssuch as calcium carbonate, calcium hydroxide, calcium lactate, calciumglycerophosphate, calcium acetate, magnesium carbonate, magnesiumhydroxide, magnesium silicate, magnesium aluminate, aluminum hydroxideor aluminum magnesium hydroxide. A particular alkali earth metal saltuseful for making an antacid tablet is calcium carbonate.

[0129] An example of a low density alkali earth metal salt useful formaking the granules according to the present invention is extra lightcalcium carbonate available from Specialty Minerals Inc., Adams, Me. Thedensity of the extra light calcium carbonate, prior to being processedaccording to the present invention, is about 0.37 g/ml. Other acceptablebuffers are provided throughout this application.

[0130] The granules used to make the tablets according to one embodimentof the present invention are made by either spray drying orpre-compacting the raw materials. Prior to being processed into granulesby either process, the density of the alkali earth metal salts useful inthe present invention ranges from about 0.3 g/ml to about 0.55 g/ml,preferably about 0.35 g/ml to about 0.45 g/ml, even more preferablyabout 0.37 g/ml to about 0.42 g/ml.

[0131] Additionally, the present invention can be manufactured byutilizing micronized compounds in place of the granules or powder.Micronization is the process by which solid drug particles are reducedin size. Since the dissolution rate is directly proportional to thesurface area of the solid, and reducing the particle size increases thesurface area, reducing the particle size increases the dissolution rate.Although micronization results in increased surface area possiblycausing particle aggregation, which can negate the benefit ofmicronization and is an expensive manufacturing step, it does have thesignificant benefit of increasing the dissolution rate of relativelywater insoluble drugs, such as omeprazole and other proton pumpinhibiting agents.

[0132] Although the tablets of this invention are primarily intended asa suspension dosage form, the granulations used to form the tablet mayalso be used to form rapidly disintegrating chewable tablets, lozenges,troches, or swallowable tablets. Therefore, the intermediateformulations as well as the process for preparing them provideadditional novel aspects of the present invention.

[0133] Effervescent tablets and powders are also prepared in accordancewith the present invention. Effervescent salts have been used todisperse medicines in water for oral administration. Effervescent saltsare granules or coarse powders containing a medicinal agent in a drymixture, usually composed of sodium bicarbonate, citric acid andtartaric acid. When the salts are added to water, the acids and the basereact to liberate carbon dioxide gas, thereby causing “effervescence.”

[0134] The choice of ingredients for effervescent granules depends bothupon the requirements of the manufacturing process and the necessity ofmaking a preparation which dissolves readily in water. The two requiredingredients are at least one acid and at least one base. The basereleases carbon dioxide upon reaction with the acid. Examples of suchacids include, but are not limited to, tartaric acid and citric acid.Preferably, the acid is a combination of both tartaric acid and citricacid. Examples of bases include, but are not limited to, sodiumcarbonate, potassium bicarbonate and sodium bicarbonate. Preferably, thebase is sodium bicarbonate, and the effervescent combination has a pH ofabout 6.0 or higher.

[0135] Effervescent salts preferably include the following ingredients,which actually produce the effervescence: sodium bicarbonate, citricacid and tartaric acid. When added to water the acids and base react toliberate carbon dioxide, resulting in effervescence. It should be notedthat any acid-base combination which results in the liberation of carbondioxide could be used in place of the combination of sodium bicarbonateand citric and tartaric acids, as long as the ingredients were suitablefor pharmaceutical use, and result in a pH of about 6.0 or higher.

[0136] It should be noted that it requires 3 molecules of NaHCO₃ toneutralize 1 molecule of citric acid and 2 molecules of NaHCO₃ toneutralize 1 molecule of tartaric acid. It is desired that theapproximate ratio of ingredients is as follows:

[0137] Citric Acid:Tartaric Acid:Sodium Bicarbonate=1:2:3.44 (byweight). This ratio can be varied and continue to produce an effectiverelease of carbon dioxide. For example, ratios of about 1:0:3 or 0:1:2are also effective.

[0138] The method of preparation of the effervescent granules of thepresent invention employs three basic processes: wet and drygranulation, and fusion. The fusion method is used for the preparationof most commercial effervescent powders. It should be noted thatalthough these methods are intended for the preparation of granules, theformulations of effervescent salts of the present invention could alsobe prepared as tablets, according to well known prior art technology fortablet preparation.

[0139] Wet granulation is the oldest method of granule preparation. Theindividual steps in the wet granulation process of tablet preparationinclude milling and sieving of the ingredients; dry powder mixing; wetmassing; granulation; and final grinding.

[0140] Dry granulation involves compressing a powder mixture into arough tablet or “slug” on a heavy-duty rotary tablet press. The slugsare then broken up into granular particles by a grinding operation,usually by passage through an oscillation granulator. The individualsteps include mixing of the powders; compressing (slugging); andgrinding (slug reduction or granulation). No wet binder or moisture isinvolved in any of the steps.

[0141] The fusion method is the most preferred method for preparing thegranules of the present invention. In this method, the compressing(slugging) step of the dry granulation process is eliminated. Instead,the powders are heated in an oven or other suitable source of heat.

[0142] IV. Proton Pump Inhibitors Administered with Parietal CellActivators

[0143] Applicant has unexpectedly discovered that certain compounds,such as chocolate, calcium and sodium bicarbonate and other alkalinesubstances, stimulate the parietal cells and enhance the pharmacologicactivity of the proton pump inhibitor administered. For the purposes ofthis application, “parietal cell activator” or “activator” shall meanany compound or mixture of compounds possessing such stimulatory effectincluding, but not limited to, chocolate, sodium bicarbonate, calcium(e.g., calcium carbonate, calcium gluconate, calcium hydroxide, calciumacetate and calcium glycerophosphate), peppermint oil, spearmint oil,coffee, tea and colas (even if decaffeinated), caffeine, theophylline,theobromine, and amino acids (particularly aromatic amino acids such asphenylalanine and tryptophan) and combinations thereof, and the saltsthereof.

[0144] Such parietal cell activators are administered in an amountsufficient to produce the desired stimulatory effect without causinguntoward side effects to subjects. For example, chocolate, as raw cocoa,is administered in an amount of about 5 mg to 2.5 g per 20 mg dose ofomeprazole (or equivalent pharmacologic dose of other proton pumpinhibitor). The dose of activator administered to a mammal, particularlya human, in the context of the present invention should be sufficient toeffect a therapeutic response (i.e., enhanced effect of proton pumpinhibitor) over a reasonable time frame. The dose will be determined bythe strength of the particular compositions employed and the conditionof the person, as well as the body weight of the person to be treated.The size of the dose also will be determined by the existence, nature,and extent of any adverse side effects that might accompany theadministration of a particular composition.

[0145] The approximate effective ranges for various parietal cellactivators per 20 mg dose of omeprazole (or equivalent dose of otherproton pump inhibitor) are: Chocolate (raw cocoa)   5 mg to 2.5 g Sodiumbicarbonate   7 mEq to 25 mEq Calcium carbonate   1 mg to 1.5 g Calciumgluconate   1 mg to 1.5 g Calcium lactate   1 mg to 1.5 g Calciumhydroxide   1 mg to 1.5 g Calcium acetate 0.5 mg to 1.5 g Calciumglycerophosphate 0.5 mg to 1.5 g Peppermint oil (powdered form)   1 mgto 1 g Spearmint oil (powdered form)   1 mg to 1 g Coffee  20 ml to 240ml Tea  20 ml to 240 ml Cola  20 ml to 240 ml Caffeine 0.5 mg to 1.5 gTheophylline 0.5 mg to 1.5 g Theobromine 0.5 mg to 1.5 g Phenylalanine0.5 mg to 1.5 g Tryptophan 0.5 mg to 1.5 g

[0146] Pharmaceutically acceptable carriers are well-known to those whoare skilled in the art. The choice of carrier will be determined, inpart, both by the particular composition and by the particular methodused to administer the composition. Accordingly, there is a wide varietyof suitable formulations of the pharmaceutical compositions of thepresent invention.

V. EXAMPLES

[0147] The present invention is further illustrated by the followingformulations, which should not be construed as limiting in any way. Thepractice of the present invention will employ, unless otherwiseindicated, conventional techniques of pharmacology and pharmaceutics,which are within the skill of the art.

Example I

[0148] A. Fast Disintegrating Suspension Tablets of Omeprazole.

[0149] A fast disintegrating tablet is compounded as follows:Croscarmellose sodium 300 g is added to the vortex of a rapidly stirredbeaker containing 3.0 kg of deionized water. This slurry is mixed for 10minutes. Omeprazole 90 g (powdered) is placed in the bowl of a Hobartmixer. After mixing, the slurry of croscarmellose sodium is added slowlyto the omeprazole in the mixer bowl, forming a granulation, which isthen placed in trays and dried at 70° C. for three hours. The drygranulation is then placed in a blender, and to it is added 1,500 g ofAvicel® AC-815 (85% microcrystalline cellulose coprocessed with 15% of acalcium, sodium alginate complex) and 1,500 g of Avicel® PH-302(microcrystalline cellulose). After this mixture is thoroughly blended,35 g of magnesium stearate is added and mixed for 5 minutes. Theresulting mixture is compressed into tablets on a standard tablet press(Hata HS). These tablets have an average weight of about 0.75 g, andcontain about 20 mg omeprazole. These tablets have low friability andrapid disintegration time. This formulation may be dissolved in anaqueous solution containing a buffering agent for immediate oraladministration.

[0150] Alternatively, the suspension tablet may be swallowed whole witha solution of buffering agent. In both cases, the preferred solution issodium bicarbonate 8.4%. As a further alternative, sodium bicarbonatepowder (about 975 mg per 20 mg dose of omeprazole (or an equipotentamount of other proton pump inhibitor) is compounded directly into thetablet. Such tablets are then dissolved in water or sodium bicarbonate8.4%, or swallowed whole with an aqueous diluent.

[0151] B1. 10 mg Tablet Formula. Omeprazole 10 mg (or lansoprazole orpantoprazole or other proton pump inhibitor in an equipotent amount)Calcium lactate 175 mg Calcium glycerophosphate 175 mg Sodiumbicarbonate 250 mg Aspartame calcium (phenylalanine) 0.5 mg Colloidalsilicon dioxide 12 mg Corn starch 15 mg Croscarmellose sodium 12 mgDextrose 10 mg Peppermint 3 mg Maltodextrin 3 mg Mannitol 3 mgPregelatinized starch 3 mg

[0152] B2. 10 mg Tablet Formula. Proton pump inhibitor: one of thefollowing: Omeprazole 10 mg Lansoprazole 15 mg Pantoprazole sodium 20 mgRabeprazole sodium 10 mg Other proton pump inhibitor in an equipotentamount Calcium lactate 375 mg Calcium glycerophosphate 375 mg Aspartamecalcium (phenylalanine) 0.5 mg Colloidal silicon dioxide 12 mg Cornstarch 15 mg Croscarmellose sodium 12 mg Dextrose 10 mg Peppermint 3 mgMaltodextrin 20 mg Mannitol 30 mg Pregelatinized starch 30 mg

[0153] B3. 10 mg Tablet Formula. Proton pump inhibitor: one of thefollowing: Omeprazole 10 mg Lansoprazole 15 mg Pantoprazole sodium 20 mgRabeprazole sodium 10 mg Other proton pump inhibitor in an equipotentamount Sodium bicarbonate 750 mg Aspartame sodium (phenylalanine) 0.5 mgColloidal silicon dioxide 12 mg Corn starch 15 mg Croscarmellose sodium12 mg Dextrose 10 mg Peppermint 3 mg Maltodextrin 20 mg Mannitol 30 mgPregelatinized starch 30 mg

[0154] C1. 20 mg Tablet Formula. Omeprazole 20 mg(or lansoprazole orpantoprazole or other proton pump inhibitor in an equipotent amount)Calcium lactate 175 mg Calcium glycerophosphate 175 mg Sodiumbicarbonate 250 mg Aspartame calcium (phenylalanine) 0.5 mg Colloidalsilicon dioxide 12 mg Corn starch 15 mg Croscarmellose sodium 12 mgDextrose 10 mg Calcium hydroxide 10 mg Peppemint 3 mg Maltodextrin 3 mgMannitol 3 mg Pregelatinized starch 3 mg

[0155] C2. 20 mg Tablet Formula. Proton pump inhibitor: One of thefollowing: Omeprazole 20 mg Lansoprazole 30 mg Pantoprazole 40 mg Otherproton pump inhibitor in an equipotent amount Calcium lactate 375 mgCalcium glycerophosphate 375 mg Aspartame calcium (phenylalanine) 0.5 mgColloidal silicon dioxide 12 mg Corn starch 15 mg Croscarmellose sodium12 mg Dextrose 10 mg Peppermint 3 mg Maltodextrin 20 mg Mannitol 30 mgPregelatinized starch 30 mg

[0156] C3. 20 mg Tablet Formula. Proton pump inhibitor: One of thefollowing: Omeprazole 20 mg Lansoprazole 30 mg Pantoprazole 40 mg Otherproton pump inhibitor in an equipotent amount Sodium bicarbonate 750 mgAspartame sodium (phenylalanine) 0.5 mg Colloidal silicon dioxide 12 mgCorn starch 15 mg Croscarmellose sodium 12 mg Dextrose 10 mg Peppermint3 mg Maltodextrin 20 mg Mannitol 30 mg Pregelatinized starch 30 mg

[0157] D1. Tablet for Rapid Dissolution. Omeprazole 20 mg (orlansoprazole or pantoprazole or other proton pump inhibitor in anequipotent amount) Calcium lactate 175 mg Calcium glycerophosphate 175mg Sodium bicarbonate 500 mg Calcium hydroxide 50 mg Croscarmellosesodium 12 mg

[0158] D2. Tablet for Rapid Dissolution. Proton pump inhibitor: One ofthe following: Omeprazole 20 mg Lansoprazole 30 mg Pantoprazole 40 mgRabeprazole sodium 20 mg Esomeprazole magnesium 20 mg Other proton pumpinhibitor in an equipotent amount Calcium lactate 300 mg Calciumglycerophosphate 300 mg Calcium hydroxide 50 mg Croscarmellose sodium 12mg

[0159] D3. Tablet for Rapid Dissolution. Proton pump inhibitor: One ofthe following: Omeprazole 20 mg Lansoprazole 30 mg Pantoprazole 40 mgRabeprazole sodium 20 mg Esomeprazole magnesium 20 mg Other proton pumpinhibitor in an equipotent amount Sodium bicarbonate 700 mg Trisodiumphosphate dodecahydrate 100 mg Croscarmellose sodium 12 mg

[0160] E1. Powder for Reconstitution for Oral Use (or per ng tube).Omeprazole 20 mg (or lansoprazole or pantoprazole or other proton pumpinhibitor in an equipotent amount) Calcium lactate 175 mg Calciumglycerophosphate 175 mg Sodium bicarbonate 500 mg Calcium hydroxide 50mg Glycerine 200 mg

[0161] E2. Powder for Reconstitution for Oral Use (or per ng tube).Proton pump inhibitor: One of the following: Omeprazole 20 mgLansoprazole 30 mg Pantoprazole 40 mg Rabeprazole sodium 20 mgEsomeprazole magnesium 20 mg

[0162] Other proton pump inhibitor in an equipotent amount Calciumlactate 300 mg Calcium glycerophosphate 300 mg Calcium hydroxide 50 mgGlycerine 200 mg

[0163] E3. Powder for Reconstitution for Oral Use (or per ng tube).Proton pump inhibitor: One of the following: Omeprazole 20 mgLansoprazole 30 mg Pantoprazole 40 mg Rabeprazole sodium 20 mgEsomeprazole magnesium 20 mg Other proton pump inhibitor in anequipotent amount Sodium bicarbonate 850 mg Trisodium phosphate 50 mg

[0164] F1. 10 mg Tablet Formula. Omeprazole 10 mg (or lansoprazole orpantoprazole or other proton pump inhibitor in an equipotent amount)Calcium lactate 175 mg Calcium glycerophosphate 175 mg Sodiumbicarbonate 250 mg Polyethylene glycol 20 mg Croscarmellose sodium 12 mgPeppermint 3 mg Magnesium silicate 1 mg Magnesium stearate 1 mg

[0165] F2. 10 mg Tablet Formula. Proton pump inhibitor: One of thefollowing: Omeprazole 10 mg Lansoprazole 15 mg Pantoprazole sodium 20 mgRabeprazole sodium 10 mg Esomeprazole magnesium 10 mg Other proton pumpinhibitor in an equipotent amount Calcium lactate 475 mg Calciumglycerophosphate 250 mg Polyethylene glycol 20 mg Croscarmellose sodium12 mg Peppermint 3 mg Magnesium silicate 10 mg Magnesium stearate 10 mg

[0166] F3. 10 mg Tablet Formula. Proton pump inhibitor: One of thefollowing: Omeprazole 10 mg Lansoprazole 15 mg Pantoprazole sodium 20 mgRabeprazole sodium 10 mg Esomeprazole magnesium 10 mg Other proton pumpinhibitor in an equipotent amount Sodium bicarbonate 700 mg Polyethyleneglycol 20 mg Croscarmellose sodium 12 mg Peppermint 3 mg Magnesiumsilicate 10 mg Magnesium stearate 10 mg

[0167] G1. 10 mg Tablet Formula. Omeprazole 10 mg (or lansoprazole orpantoprazole or other proton pump inhibitor in an equipotent amount)Calcium lactate 200 mg Calcium glycerophosphate 200 mg Sodiumbicarbonate 400 mg Croscarmellose sodium 12 mg Pregelatinized starch 3mg

[0168] G2. 10 mg Tablet Formula. Proton pump inhibitor: One of thefollowing: Omeprazole 10 mg Lansoprazole 15 mg Pantoprazole sodium 20 mgRabeprazole sodium 10 mg Esomeprazole magnesium 10 mg Other proton pumpinhibitor in an equipotent amount Calcium lactate 400 mg Calciumglycerophosphate 400 mg Croscarmellose sodium 12 mg Pregelatinizedstarch 3 mg

[0169] G3. 10 mg Tablet Formula. Proton pump inhibitor: One of thefollowing: Omeprazole 10 mg Lansoprazole 15 mg Pantoprazole sodium 20 mgRabeprazole sodium 10 mg Esomeprazole magnesium 10 mg Other proton pumpinhibitor in an equipotent amount Sodium bicarboante 750 mgCroscarmellose sodium 12 mg Pregelatinized starch 3 mg

[0170] All of the tablets and powders of this Example may be swallowedwhole, chewed or mixed with an aqueous medium prior to administration.

Example II

[0171] Standard Tablet of Proton Pump Inhibitor and Buffering Agent.

[0172] Ten (10) tablets were prepared using a standard tablet press,each tablet comprising about 20 mg omeprazole and about 975 mg sodiumbicarbonate uniformly dispersed throughout the tablet. To test thedisintegration rate of the tablets, each was added to 60 ml of water.Using previously prepared liquid omeprazole/sodium bicarbonate solutionas a visual comparator, it was observed that each tablet was completelydispersed in under three (3) minutes.

[0173] Another study using the tablets compounded according to thisExample evaluated the bioactivity of the tablets in five (5) adultcritical care subjects. Each subject was administered one tablet via ngwith a small amount of water, and the pH of ng aspirate was monitoredusing paper measure. The pH for each subject was evaluated for 6 hoursand remained above 4, thus demonstrating the therapeutic benefit of thetablets in these patients.

[0174] Tablets were also prepared by boring out the center of sodiumbicarbonate USP 975 mg tablets with a knife. Most of the removed sodiumbicarbonate powder was then triturated with the contents of a 20 mgPrilosec® capsule and the resulting mixture was then packed into thehole in the tablet and sealed with glycerin.

Example III

[0175] Proton Pump Inhibitor Central Core Tablet.

[0176] Tablets are prepared in a two-step process. First, about 20 mg ofomeprazole is formed into a tablet as is known in the art to be used asa central core. Second, about 975 mg sodium bicarbonate USP is used touniformly surround the central core to form an outer protective cover ofsodium bicarbonate. The central core and outer cover are both preparedusing standard binders and other excipients to create a finished,pharmaceutically acceptable tablet. The tablets may be swallowed wholewith a glass of water.

Example IV

[0177] Effervescent Tablets and Granules.

[0178] The granules of one 20mg Prilosec® capsule were emptied into amortar and triturated with a pestle to a fine powder. The omeprazolepowder was then geometrically diluted with about 958 mg sodiumbicarbonate USP, about 832 mg citric acid USP and about 312 mg potassiumcarbonate USP to form a homogeneous mixture of effervescent omeprazolepowder. This powder was then added to about 60 ml of water whereupon thepowder reacted with the water to create effervescence. A bubblingsolution resulted of omeprazole and principally the antacids sodiumcitrate and potassium citrate. The solution was then administered orallyto one adult male subject and gastric pH was measured using pHydrionpaper. The results were as follows: Time Interval pH MeasuredImmediately prior to dose 2 1 hour post dose 7 2 hours post dose 6 4hours post dose 6 6 hours post dose 5 8 hours post dose 4

[0179] One skilled in the art of pharmaceutical compounding willappreciate that bulk powders can be manufactured using the above ratiosof ingredients, and that the powder can be pressed into tablets usingstandard binders and excipients. Such tablets are then mixed with waterto activate the effervescent agents and create the desired solution. Inaddition, lansoprazole 30 mg (or an equipotent dose of other proton pumpinhibitor) can be substituted for omeprazole.

[0180] The effervescent powder and tablets can alternatively beformulated by employing the above mixture but adding an additional 200mg of sodium bicarbonate USP to create a resulting solution with ahigher pH. Further, instead of the excess 200 mg of sodium bicarbonate,100 mg of calcium glycerophosphate or 100 mg of calcium lactate can beemployed. Combinations of the same can also added.

Example V

[0181] Parietal Cell Activator “Choco-Base™” Formulations and Efficacy.

[0182] Children are affected by gastro esophageal reflux disease (GERD)with atypical manifestations. Many of these atypical symptoms aredifficult to control with traditional drugs such as H₂-antagonists,cisapride, or sucralfate. Proton pump inhibiting agents are moreeffective in controlling gastric pH and the symptoms of gastroesophagealreflux disease than other agents. However, proton pump inhibiting agentsare not available in dosage forms that are easy to administer to youngchildren. To address this problem, applicant employed omeprazole orlansoprazole in a buffered chocolate suspension (Choco-Base), inchildren with manifestations of gastroesophageal reflux disease.

[0183] Applicant performed a retrospective evaluation of children withgastroesophageal reflux disease referred to the University ofMissouri-Columbia from 1995 to 1998. who received treatment with theexperimental omeprazole or lansoprazole Choco-Base suspension formulatedin accordance with Formulation 1 stated below. Data were included on allpatients with follow up information sufficient to draw conclusions aboutpre/post treatment (usually>6 months). There were 25 patients who metthe criteria for this evaluation. Age range was several weeks to greaterthan 5 years. Most patients had a history of numerous unsuccessfulattempts at ameliorating the effects of gastroesophageal reflux disease.Medication histories indicated many trials of various drugs.

[0184] The primary investigator reviewed all charts for uniformity ofdata collection. When insufficient data was available in the Universitycharts, attempts were made to review charts in the local primary carephysicians' offices for follow-up data. If information was stillunavailable to review, attempts were made to contact family forfollow-up. If data were still unavailable the patients were consideredinevaluable.

[0185] Patient charts were reviewed in detail. Data noted were date ofcommencement of therapy, date of termination of therapy and any reasonfor termination other than response to treatment. Patient demographicswere also recorded, as were any other medical illnesses. Medicalillnesses were divided grossly into those that are associated with orexacerbate gastroesophageal reflux disease and those that do not.

[0186] Patient charts were examined for evidence of response to therapy.As this was largely a referral population, and a retrospective review,quantification of symptomatology based on scores, office visits and EDvisits was difficult. Therefore, applicant examined charts for evidenceof an overall change in patient symptoms. Any data to point towardsimprovement, decline or lack of change were examined and recorded.

[0187] Results.

[0188] A total of 33 pediatric patients to date have been treated withthe above-described suspension at the University of Missouri—Columbia.Of the 33 patients, 9 were excluded from the study, all based uponinsufficient data about commencement, duration or outcome in treatmentwith proton pump inhibitor therapy. This left 24 patients with enoughdata to draw conclusions.

[0189] Of the 24 remaining patients, 18 were males and 6 females. Agesat implementation of proton pump inhibitor therapy ranged from 2 weeksof age to 9 years old. Median age at start of therapy was 26.5 months[mean of 37 mo.]. Early on, reflux was usually documented by endoscopyand confirmed by pH probe. Eventually, pH probe was dropped andendoscopy was the sole method for documenting reflux, usually at thetime of another surgery (most often T-tubes or adenoidectomy). Sevenpatients had pH probe confirmation of gastroesophageal reflux disease,whereas 18 had endoscopic confirmation of reflux including all eight whohad pH probing done (See FIG. 5 and 6). Reflux was diagnosed onendoscopy most commonly by cobblestoning of the tracheal wall, withlaryngeal and pharyngeal cobblestoning as findings in a few patients.Six patients had neither pH nor endoscopic documentation ofgastroesophageal reflux disease, but were tried on proton pump inhibitortherapy based on symptomatology alone.

[0190] Past medical history was identified in each chart. Ten patientshad reflux-associated diagnoses. These were most commonly cerebralpalsy, prematurity and Pierre Robin sequence. Other diagnoses wereCharcot-Marie-Tooth disease, Velocardiofacial syndrome, Down syndromeand De George's syndrome. Non-reflux medical history was also identifiedand recorded separately (See Table 2 below).

[0191] Patients were, in general, referral patients from local familypractice clinics, pediatricians, or other pediatric health careprofessionals. Most patients were referred to ENT for upper airwayproblems, sinusitis, or recurrent/chronic otitis media that had beenrefractory to medical therapy as reported by the primary care physician.Symptoms and signs most commonly found in these patients were recordedand tallied. All signs and symptoms were broken down into six majorcategories: (1) nasal; (2) otologic; (3) respiratory; (4)gastrointestinal; (5) sleep-related; and (6) other. The most commonproblems fell into one or all of the first 3 categories (See Table 1below).

[0192] Most patients had been treated in the past with medical therapyin the form of antibiotics, steroids, asthma medications and otherdiagnosis-appropriate therapies. In addition, nine of the patients hadbeen on reflux therapy in the past, most commonly in the form ofconservative therapy such as head of bed elevation 30°, avoidance ofevening snacks, avoidance of caffeinated beverages as well as cisaprideand ranitidine (See FIG. 7).

[0193] The proton pump inhibitor suspension used in this group ofpatients was Choco-Base suspension of either lansoprazole or omeprazole.The dosing was very uniform, with patients receiving doses of either 10or 20 mg of omeprazole and 23 mg of lansoprazole. Initially, in April of1996 when therapy was first instituted 10 mg of omeprazole was used.There were 3 patients in this early phase who were treated initiallywith 10 mg po qd of omeprazole. All three subsequently were increased toeither 20 mg po qd of omeprazole or 23 mg po qd of lansoprazole. Allremaining patients were given either the 20 mg omeprazole or the 23 mglansoprazole treatment qd, except in one case, where 30 mg oflansoprazole was used. Patients were instructed to take their doses onceper day, preferably at night in most cases. Suspensions were all filledthrough the University of Missouri Pharmacy at Green Meadows. Thisallowed for tracking of usage through refill data.

[0194] Most patients responded favorably to and tolerated the once dailydosing of Choco-Base proton pump inhibitor suspension. Two patients haddocumented adverse effects associated with the use of the proton pumpinhibitor suspension. In one patient, the mother reported increasedburping up and dyspepsia, which was thought to be related to treatmentfailure. The other patient had small amounts of bloody stools permother. This patient never had his stool tested, as his bloody stoolpromptly resolved upon cessation of therapy, with no further sequellae.The other 23 patients had no documented adverse effects.

[0195] Patients were categorized based on review of clinic notes andchart review into general categories: (1) improved; (2) unchanged; (3)failed; and (4) inconclusive. Of 24 patients with sufficient data forfollow up, 18 showed improvement in symptomatology upon commencement ofproton pump inhibitor therapy [72%]. The seven who did not respond wereanalyzed and grouped. Three showed no change in symptomatology andclinical findings while on therapy, one complained of worsening symptomswhile on therapy, one patient had therapy as prophylaxis for surgery,and two stopped therapy just after its commencement (see FIG. 8).Setting aside the cases in which therapy was stopped before conclusionscould be drawn and the case in which proton pump inhibitor therapy wasfor purely prophylactic reasons, leaves (17/21) 81% of patients thatresponded to Choco-Base suspension. This means that 19% (4/21) ofpatients received no apparent benefit from proton pump inhibitortherapy. Of all these patients, only 4% complained of worsening symptomsand the side effects were 4% (1/21) and were mild bloody stool thatcompletely resolved upon cessation of therapy.

[0196] Discussion.

[0197] Gastroesophageal reflux disease in the pediatric population isrelatively common, affecting almost 50% of newborns. Even though mostinfants outgrow physiologic reflux, pathologic reflux still affectsapproximately 5% of all children throughout childhood. Recentlyconsiderable data has pointed to reflux as an etiologic factor inextra-esophageal areas gastroesophageal reflux disease has beenattributed to sinusitis, dental caries, otitis media, asthma, apnea,arousal, pneumonia, bronchitis, and cough, among others. Despite thecommon nature of reflux, there seems to have been little improvement intherapy for reflux, especially in the non-surgical arena.

[0198] The standard of therapy for the treatment of gastroesophagealreflux disease in the pediatric population has become a progression fromconservative therapy to a combination of a pro-kinetic agent and H-2blocker therapy. Nonetheless, many patients fail this treatment protocoland become surgical candidates. In adults, proton pump inhibitor therapyis effective in 90% of those treated for gastroesophageal refluxdisease. As a medical alternative to the H-2 blockers, the proton pumpinhibiting agents have not been studied extensively in the pediatricpopulation. Part of the reason for this lack of data may be related tothe absence of a suitable dosage formulation for this very youngpopulation, primarily under 2 years of age, that does not swallowcapsules or tablets. It would be desirable to have a true liquidformulation (solution or suspension) with good palatability such as isused for oral antibiotics, decongestants, antihistamines, H-2 blockers,cisapride, metoclopramide, etc. The use of lansoprazole granules(removed from the gelatin capule) and sprinkled on applesauce has beenapproved by the Food and Drug Administration as an alternative method ofdrug administration in adults but not in children. Published data arelacking on the efficacy of the lansoprazole sprinkle method in children.Omeprazole has been studied for bioequivalence as a sprinkle in adultsand appears to produce comparable serum concentrations when compared tothe standard capsule. Again no data are available on the omeprazolesprinkle in children. An additional disadvantage of omeprazole is itstaste which is quinine-like. Even when suspended in juice, applesauce orthe like, the bitter nature of the medicine is easily tasted even if onegranule is chewed. For this reason applicant eventually progressed touse lansoprazole in Choco-Base. Pantoprazole and rabeprazole areavailable as enteric-coated tablets only. Currently, none of the protonpump inhibiting agents available in the United States are approved forpediatric use. There is some controversy as to what the appropriatedosage should be in this group of patients. A recent review by IsraelD., et al. suggests that effective proton pump inhibitor dosages shouldbe higher than that originally reported, i.e., from 0.7 mg/kg to 2 or 3mg/kg omeprazole. Since toxicity with the proton pump inhibiting agentsis not seen even at >50 mg/kg, there appears little risk associated withthe higher dosages. Based on observations at the University of Missouriconsistent with the findings of this review, applicant established asimple fixed dosage regimen of 10 ml Choco-Base suspension daily. This10 ml dose provided 20 mg omeprazole or 23 mg lansoprazole.

[0199] In the ICU setting, the University of Missouri—Columbia has beenusing an unflavored proton pump inhibitor suspension given once dailyper various tubes (nasogastric, g-tube, jejunal feeding tube, duo tube,etc.) for stress ulcer prophylaxis. It seemed only logical that if thistherapy could be made into a palatable form, it would have many idealdrug characteristics for the pediatric population. First, it would beliquid, and therefore could be administered at earlier ages. Second, ifmade flavorful it could help to reduce noncompliance. Third, it couldafford once daily dosing, also helping in reducing noncompliance. In theprocess, applicant discovered that the dosing could be standardized,which nearly eliminated dosing complexity.

[0200] Choco-Base is a product which protects drugs which are acidlabile, such as proton pump inhibiting agents, from acid degradation.The first few pediatric patients with reflux prescribed Choco-Base weresicker patients. They had been on prior therapy and had been diagnosedboth by pH probe and endoscopy. In the first few months, applicanttreated patients with 10 mg of omeprazole qd (1 mg/kg) and found this tobe somewhat ineffective, and quickly increased the dosing to 20 mg (2mg/kg) of omeprazole. About halfway through the study, applicant beganusing lansoprazole 23 mg po qd. Applicant's standard therapy was theneither 20 mg of omeprazole or 23 mg of lansoprazole once daily. Theextra 3 mg of lansoprazole is related only to the fact that the finalconcentration was 2.25 mg/ml, and applicant desired to keep dosingsimple, so he used a 10 ml suspension.

[0201] The patients that were treated represented a tertiary care centerpopulation, and they were inherently sicker and refractory to medicaltherapy in the past. The overall 72% success rate is slightly lower thanthe 90% success rates of proton pump inhibiting agents in the adultpopulation, but this can be attributed to the refractory nature of theirillness, most having failed prior non- proton pump inhibitor treatment.The population in this study is not indicative of general practicepopulations.

[0202] Conclusion.

[0203] Proton pump inhibitor therapy is a beneficial therapeutic optionin the treatment of reflux related symptoms in the pediatric population.Its once daily dosing and standard dosing scheme combined with apalatable formulation makes it an ideal pharmacologic agent. TABLE 1Symptoms Patient Numbers Nasal: 35 Sinusitis 7 Congestion 8 Nasaldischarge 16 Other 4 Otologic: 26 Otitis Media 17 Otorrhea 9Respiratory: 34 Cough 10 Wheeze 11 Respiratory Distress: 5 Pneumonia 2Other 6 Gastrointestinal: 10 Abdominal Pain 1 Reflux/Vomiting 4 Other 4Sleep Disturbances: 11 Other 2

[0204] TABLE 2 Reflux Associated: 12 Premature 5 Pierre-Robin 2 CerebralPalsy 2 Down Syndrome 1 Charcot-Marie-Tooth 1 Velocardiofacial Syndrome1 Other Medical History 12 Cleft Palate 3 Asthma 3 Autism 2 SeizureDisorder 1 Diabetes Mellitus 1 Subglottic Stenosis 1 TracheostomyDependent 1

[0205] FORMULATION 1 PART A INGREDIENTS AMOUNT (mg) Omeprazole 200Sucrose 26000 Sodium Bicarbonate 9400 Cocoa 1800 Corn Syrup Solids 6000Sodium Caseinate 1000 Soy Lecithin 150 Sodium Chloride 35 TricalciumPhosphate 20 Dipotassium Phosphate 12 Silicon Dioxide 5 Sodium StearoylLactylate 5 PART B INGREDIENTS AMOUNT (ml) Distilled Water 100COMPOUNDING INSTRUCTIONS Add Part B to Part A to create a total volumeof approximately 130 ml with an omeprazole concentration of about 1.5mg/ml.

[0206] FORMULATION 2 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000Cocoa 1800 Corn Syrup Solids 6000 Sodium Caseinate 1000 Soy Lecithin 150Sodium Chloride 35 Tricalcium Phosphate 20 Dipotassium Phosphate 12Silicon Dioxide 5 Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNTDistilled Water  100 ml Sodium Bicarbonate 8400 mg Omeprazole  200 mgCOMPOUNDING INSTRUCTIONS Mix the constituents of Part B togetherthoroughly and then add to Part A. This results in a total volume ofapproximately 130 ml with an omeprazole concentration of about 1.5mg/ml.

[0207] FORMULATION 3 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000Sodium Bicarbonate 9400 Cocoa 1800 Corn Syrup Solids 6000 SodiumCaseinate 1000 Soy Lecithin 150 Sodium Chloride 35 Tricalcium Phosphate20 Dipotassium Phosphate 12 Silicon Dioxide 5 Sodium Stearoyl Lactylate5 PART B INGREDIENTS AMOUNT Distilled Water 100 ml Omeprazole 200 mgCOMPOUNDING INSTRUCTIONS This formulation is reconstituted at the timeof use by a pharmacist. Part B is mixed first and is then uniformlymixed with the components of Part A. A final volume of about 130 ml iscreated having an omeprazole concentration of about 1.5 mg/ml.

[0208] FORMULATION 4 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000Cocoa 1800 Corn Syrup Solids 6000 Sodium Caseinate 1000 Soy Lecithin 150Sodium Chloride 35 Tricalcium Phosphate 20 Dipotassium Phosphate 12Silicon Dioxide 5 Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNTDistilled Water  100 ml Sodium Bicarbonate 8400 mg Omeprazole  200 mgCOMPOUNDING INSTRUCTIONS This formulation is reconstituted at the timeof use by a pharmacist. Part B is mixed first and is then uniformlymixed with the components of Part A. A final volume of about 130 ml iscreated having an omeprazole concentration of about 1.5 mg/ml.

[0209] In all four of the above formulations, lansoprazole or otherproton pump inhibitor can be substituted for omeprazole in equipotentamounts. For example, 300 mg of lansoprazole may be substituted for the200 mg of omeprazole. Additionally, aspartame can be substituted forsucrose, and the following other ingredients can be employed ascarriers, adjuvants and excipients: maltodextrin, vanilla, carrageenan,mono and diglycerides, and lactated monoglycerides. One skilled in theart will appreciate that not all of the ingredients are necessary tocreate a Choco-Base formulation that is safe and effective.

[0210] Omeprazole powder or enteric-coated granules can be used in eachformulation. If the enteric-coated granules are used, the coating iseither dissolved by the aqueous diluent or inactivated by trituration inthe compounding process.

[0211] Applicant additionally analyzed the effects of a lansoprazoleChoco-Base formulation on gastric pH using a pH meter (FisherScientific) in one adult patient versus lansoprazole alone. The patientwas first given a 30 mg oral capsule of lansoprazole (Prevacid®), andthe patient's gastric pH was measured at 0, 4, 8, 12, and 16 hours postdose. The results are illustrated in FIG. 4.

[0212] The ChocoBase product was compounded according to Formulation 1above, except 300 mg of lansoprazole was used instead of omeprazole. Adose of 30 mg lansoprazole Choco-Base was orally administered at hour 18post lansoprazole alone. Gastric pH was measured using a pH meter athours 18, 19, 24, 28, 32, 36, 40, 48, 52, and 56 post lansoprazole alonedose.

[0213]FIG. 4 illustrates the lansoprazole/cocoa combination resulted inhigher pHs at hours 19-56 than lansoprazole alone at hours 4-18.Therefore, the combination of the lansoprazole with chocolate enhancedthe pharmacologic activity of the lansoprazole. The results establishthat the sodium bicarbonate as well as chocolate flavoring and calciumwere all able to stimulate the activation of the proton pumps, perhapsdue to the release of gastrin. Proton pump inhibiting agents work byfunctionally inhibiting the proton pump and effectively block activatedproton pumps (primarily those inserted into the secretory canalicularmembrane). By further administering the proton pump inhibitor with oneof these activators or enhancers, there is a synchronization ofactivation of the proton pump with the absorption and subsequentparietal cell concentrations of the proton pump inhibitor. Asillustrated in FIG. 4, this combination produced a much longerpharmacologic effect than when the proton pump inhibitor wasadministered alone.

Example VI

[0214] Combination Tablet Delivering Bolus And Time-Released Doses ofProton Pump Inhibitor

[0215] Tablets were compounded using known methods by forming an innercore of 10 mg omeprazole powder mixed with 750 mg sodium bicarbonate,and an outer core of 10 mg omeprazole enteric-coated granules mixed withknown binders and excipients. Upon ingestion of the whole tablet, thetablet dissolves and the inner core is dispersed in the stomach where itis absorbed for immediate therapeutic effect. The enteric-coatedgranules are later absorbed in the duodenum to provide symptomaticrelief later in the dosing cycle. This tablet is particularly useful inpatients who experience breakthrough gastritis between conventionaldoses, such as while sleeping or in the early morning hours.

Example VII

[0216] Therapeutic Application.

[0217] Patients were evaluable if they met the following criteria: hadtwo or more risk factors for SRMD (mechanical ventilation, head injury,severe burn, sepsis, multiple trauma, adult respiratory distresssyndrome, major surgery, acute renal failure, multiple operativeprocedures, coagulotherapy, significant hyportension, acid-basedisorder, and hepatic failure), gastric pH of ≦4 prior to study entry,and no concomitant prophylaxis for SRMD.

[0218] The omeprazole solution was prepared by mixing 10 ml of 8.4%sodium bicarbonate with the contents of a 20 mg capsule of omeprazole(Merck & Co. Inc., West Point, Pa.) to yield a solution having a finalomeprazole concentration of 2 mg/ml.

[0219] Nasogastric (ng) tubes were placed in the patients and anomeprazole dosage protocol of buffered 40 mg omeprazole solution (2 mgomeprazole/l ml NaHCO₃—8.4%) followed by 40 mg of the same bufferedomeprazole solution in eight hours, then 20 mg of the same bufferedomeprazole solution per day, for five days. After each bufferedomeprazole solution administration, nasogastric suction was turned offfor thirty minutes.

[0220] Eleven patients were evaluable. All patients were mechanicallyventilated. Two hours after the initial 40 mg dose of bufferedomeprazole solution, all patients had an increase in gastric pH togreater than eight as shown in FIG. 1. Ten of the eleven patientsmaintained a gastric pH of greater than or equal to four whenadministered 20 mg omeprazole solution. One patient required 40 mgomeprazole solution per day (closed head injury, five total risk factorsfor SRMD). Two patients were changed to omeprazole solution after havingdeveloped clinically significant upper gastrointestinal bleeding whilereceiving conventional intravenous H2-antagonists. Bleeding subsided inboth cases after twenty-four hours. Clinically significant uppergastrointestinal bleeding did not occur in the other nine patients.Overall mortality was 27%, mortality attributable to uppergastrointestinal bleeding was 0%. Pneumonia developed in one patientafter initiating omeprazole therapy and was present upon the initiationof omeprazole therapy in another patient. The mean length of prophylaxiswas five days.

[0221] A pharmacoeconomic analysis revealed a difference in the totalcost of care for the prophylaxis of SRMD:

[0222] ranitidine (Zantac®) continuous infusion intravenously (150 mg/24hours)×five days $125.50;

[0223] cimetidine-(Tagamet®) continuous infusion intravenously (900mg/24 hours)×five days $109.61;

[0224] sucralfate one g slurry four times a day per (ng) tube×five days$73.00; and

[0225] buffered omeprazole solution regimen per (ng) tube×five days$65.70.

[0226] This example illustrates the efficacy of the buffered omeprazolesolution of the present invention based on the increase in gastric pH,safety and cost of the buffered omeprazole solution as a method for SRMDprophylaxis.

Example VIII

[0227] Effect on pH.

[0228] Experiments were carried out in order to determine the effect ofthe omeprazole solution (2 mg omeprazole/l ml NaHCO₃—8.4%)administration on the accuracy of subsequent pH measurements through anasogastric tube.

[0229] After preparing a total of 40 mg of buffered omeprazole solution,in the manner of Example VII, doses were administered into the stomach,usually through a nasogastric (ng) tube. Nasogastric tubes from ninedifferent institutions were gathered for an evaluation. Artificialgastric fluid (gf) was prepared according to the USP. pH recordings weremade in triplicate using a Microcomputer Portable pH meter model 6007(Jenco Electronics Ltd., Taipei, Taiwan).

[0230] First, the terminal portion (tp) of the nasogastric tubes wasplaced into a glass beaker containing the gastric fluid. A 5 ml aliquotof gastric fluid was aspirated through each tube and the pH recorded;this was called the “pre-omeprazole solution/suspensionmeasurement.”Second, the terminal portion (tp) of each of thenasogastric tubes was removed from the beaker of gastric fluid andplaced into an empty beaker. Twenty (20) mg of omeprazole solution wasdelivered through each of the nasogastric tubes and flushed with 10 mlof tap water. The terminal portion (tp) of each of the nasogastric tubeswas placed back into the gastric fluid. After a one hour incubation, a 5ml aliquot of gastric fluid was aspirated through each nasogastric tubeand the pH recorded; this was called the “after first dose SOS[Simplified Omeprazole Solution] measurement.” Third, after anadditional hour had passed, the second step was repeated; this wascalled the “after second dose SOS [Simplified Omeprazole Solution]measurement.” In addition to the pre-omeprazole measurement, the pH ofthe gastric fluid was checked in triplicate after the second and thirdsteps. A change in the pH measurements of +/−0.3 units was consideredsignificant. The Friedman test was used to compare the results. TheFriedman test is a two way analysis of variance which is used when morethan two related samples are of interest, as in repeated measurements.

[0231] The results of these experiments are outlined in Table 3. TABLE 3ng1 ng2 ng3 ng4 ng5 ng6 ng7 ng8 ng9 [1] gf 1.3 1.3 1.3 1.3 1.3 1.3 1.31.3 1.3 Pre SOS [2] gf p 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1^(st) dose1.3↑ check of gf pH [3] gf p 1.3 1.3 1.4 1.4 1.4 1.3 1.4 1.3 1.3 2^(nd)Dose 1.3↑ SOS check pH = 9.0 of gf pH

[0232] Table 3 illustrates the results of the pH measurements that weretaken during the course of the experiment. These results illustrate thatthere were no statistically significant latent effects of omeprazolesolution administration (per nasogastric tube) on the accuracy ofsubsequent pH measurements obtained through the same nasogastric tube.

Example IX

[0233] Efficacy of Buffered Omeprazole Solution in Ventilated Patients.

[0234] Experiments were performed in order to determine the efficacy,safety, and cost of buffered omeprazole solution in mechanicallyventilated critically ill patients who have at least one additional riskfactor for stress-related mucosal damage.

[0235] Patients: Seventy-five adult,.mechanically ventilated patientswith at least one additional risk factor for stress-related mucosaldamage.

[0236] Interventions: Patients received 20 ml omeprazole solution(prepared as per Example VII and containing 40 mg of omeprazole)initially, followed by a second 20 ml dose six to eight hours later,then 10 ml (20 mg) daily. Omeprazole solution according to the presentinvention was administered through a nasogastric tube, followed by 5-10ml of tap water. The nasogastric tube was clamped for one to two hoursafter each administration.

[0237] Measurements and Main Results: The primary outcome measure wasclinically significant gastrointestinal bleeding determined byendoscopic evaluation, nasogastric aspirate examination, orheme-positive coffee ground material that did not clear with lavage andwas associated with a five percent decrease in hematocrit. Secondaryefficacy measures were gastric pH measured four hours after omeprazolewas first administered, mean gastric pH after omeprazole was started,and the lowest gastric pH during omeprazole therapy. Safety-relatedoutcomes included the incidence of adverse events and the incidence ofpneumonia. No patient experienced clinically significant uppergastrointestinal bleeding after receiving omeprazole suspension. Thefour-hour post omeprazole gastric pH was 7.1 (mean), the mean gastric pHafter starting omeprazole was 6.8 (mean) and the lowest pH afterstarting omeprazole was 5.6 (mean). The incidence of pneumonia wastwelve percent. No patient in this high-risk population experienced anadverse event or a drug interaction that was attributable to omeprazole.

[0238] Conclusions: Omeprazole solution prevented clinically significantupper gastrointestinal bleeding and maintained gastric pH above 5.5 inmechanically ventilated critical care patients without producingtoxicity.

[0239] Materials and Methods:

[0240] The study protocol was approved by the Institutional Review Boardfor the University of Missouri at Columbia.

[0241] Study Population: All adult (>18 years old) patients admitted tothe surgical intensive care and burn unit at the University of MissouriHospital with an intact stomach, a nasogastric tube in place, and ananticipated intensive care unit stay of at least forty-eight hours wereconsidered for inclusion in the study. To be included patients also hadto have a gastric pH of <4, had to be mechanically ventilated and haveone of the following additional risk factors for a minimum oftwenty-four hours after initiation of omeprazole suspension: head injurywith altered level of consciousness, extensive burns (>20% Body SurfaceArea), acute renal failure, acid-base disorder, multiple trauma,coagulopathy, multiple operative procedures, coma, hypotension forlonger than one hour or sepsis (see. Table 4). Sepsis was defined as thepresence of invasive pathogenic organisms or their toxins in blood ortissues resulting in a systematic response that included two or more ofthe following: temperature greater than 38° C. or less than 36° C.,heart rate greater than 90 beats/minute, respiratory rate greater than20 breaths/minute (or _(p)O₂ less than 75 mm Hg), and white blood cellcount greater than 12,000 or less than 4,000 cells/mm³ or more than 10percent bands (Bone, Let's Agree on Terminology: Definitions of Sepsis,CRIT. CARE MED., 19: 27 (1991)). Patients in whom H₂-antagonist therapyhad failed or who experienced an adverse event while receivingH₂-antagonist therapy were also included.

[0242] Patients were excluded from the study if they were receivingazole antifungal agents through the nasogastric tube; were likely toswallow blood (e.g., facial and/or sinus fractures, oral lacerations);had severe thrombocytopenia (platelet count less than 30,000 cells/mm³);were receiving enteral feedings through the nasogastric tube; or had ahistory of vagotomy, pyloroplasty, or gastroplasty. In addition,patients with a gastric pH above four for forty-eight hours after ICUadmission (without prophylaxis) were not eligible for participation.Patients who developed bleeding within the digestive tract that was notstress-related mucosal damage (e.g., endoscopically verified varicealbleeding or Mallory-Weiss tears, oral lesions, nasal tears due toplacement of the nasogastric tube) were excluded from the efficacyevaluation and categorized as having non-stress-related mucosalbleeding. The reason for this exclusion is the confounding effect ofnon-stress-related mucosal bleeding on efficacy-related outcomes, suchas the use of nasogastric aspirate inspection to define clinicallysignificant upper gastrointestinal bleeding.

[0243] Study Drug Administration: Omeprazole solution was preparedimmediately before administration by the patient's nurse using thefollowing instructions: empty the contents of one or two 20 mgomeprazole capsule(s) into an empty 10 ml syringe (with 20 gauge needlein place) from which the plunger has been removed. (Omeprazoledelayed-release capsules, Merck & Co., Inc., West Point, Pa.); replacethe plunger and uncap the needle; withdraw 10 ml of 8.4% sodiumbicarbonate solution or 20 ml if 40 mg given (Abbott Laboratories, NorthChicago, Ill.), to create a concentration of 2 mg omeprazole per ml of8.4% sodium bicarbonate; and allow the enteric coated pellets ofomeprazole to completely breakdown, 30 minutes (agitation is helpful).The omeprazole in the resultant preparation is partially dissolved andpartially suspended. The preparation should have a milky whiteappearance with fine sediment and should be shaken beforeadministration. The solution was not administered with acidicsubstances. A high-pressure liquid chromatography study was performedthat demonstrated that this preparation of simplified omeprazolesuspension maintains >90% potency for seven days at room temperature.This preparation remained free of bacterial and fungal contamination forthirty days when stored at room temperature (See Table 7).

[0244] The initial dose of omeprazole solution was 40 mg, followed by asecond 40 mg dose six to eight hours later, then a 20 mg daily doseadministered at 8:00 AM. Each dose was administered through thenasogastric tube. The nasogastric tube was then flushed with 5-10 ml oftap water and clamped for at least one hour. Omeprazole therapy wascontinued until there was no longer a need for stress ulcer prophylaxis(usually after the nasogastric tube was removed and the patient wastaking water/food by mouth, or after the patient was removed frommechanical ventilation).

[0245] Primary Outcome Measures: The primary outcome measure in thisstudy was the rate of clinically significant stress-related mucosalbleeding defined as endoscopic evidence of stress-related mucosalbleeding or bright red blood per nasogastric tube that did not clearafter a 5-minute lavage or persistent Gastroccult (SmithKlineDiagnostics, Sunnyville, Calif.) positive coffee ground material forfour consecutive hours that did not clear with lavage (at least 100 ml)and produced a 5% decrease in hematocrit.

[0246] Secondary Outcome Measures: The secondary efficacy measures weregastric pH measured four hours after omeprazole was administered, meangastric pH after starting omeprazole and lowest gastric pH duringomeprazole administration. Gastric pH was measured immediately afteraspirating gastric contents through the nasogastric tube. pH paper(pHydrion improved pH papers, Microessential Laboratory, Brooklyn, N.Y.)was used to measure gastric aspirate pH. The pH range of the test stripswas 1 to 11, in increments of one pH unit. Gastric pH was measuredbefore the initiation of omeprazole solution therapy, immediately beforeeach dose, and every four hours between doses.

[0247] Other secondary outcome measures were incidence of adverse events(including drug interactions) and pneumonia. Any adverse event thatdeveloped during the study was recorded. Pneumonia was defined usingindicators adapted from the Centers for Disease Prevention and Controldefinition of nosocormial pneumonia (Garner et al., 1988). According tothese criteria, a patient who has pneumonia is one who has rales ordullness to percussion on physical examination of the chest or has achest radiograph that shows new or progressive infiltrate(s),consolidation, cavitation, or pleural effusion and has at least two ofthe following present new purulent sputum or changes in character of thesputum, an organism isolated from blood culture, fever or leukocytosis,or evidence of infection from a protective specimen brush orbronchoalveolar lavage. Patients who met the criteria for pneumonia andwere receiving antimicrobial agents for the treatment of pneumonia wereincluded in the pneumonia incidence figure. These criteria were alsoused as an initial screen before the first dose of study drug wasadministered to determine if pneumonia was present prior to the start ofomeprazole suspension.

[0248] Cost of Care Analysis: A pharmacoeconomic evaluation of stressulcer prophylaxis using omeprazole solution was performed. Theevaluation included total drug cost (acquisition and administration),actual costs associated with adverse events (e.g., psychiatryconsultation for mental confusion), costs associated with clinicallysignificant upper gastrointestinal bleeding. Total drug cost wascalculated by adding the average institutional costs of omeprazole 20 mgcapsules, 50 ml sodium bicarbonate vials, and 10 ml syringes withneedle; nursing time (drug administration, pH monitoring); pharmacy time(drug preparation); and disposal costs. Costs associated with clinicallysignificant upper gastrointestinal bleeding included endoscopy chargesand accompanying consultation fees, procedures required to stop thebleeding (e.g., surgery, hemostatic agents, endoscopic procedures),increased hospital length of stay (as assessed by the attendingphysician), and cost of drugs used to treat the gastrointestinalbleeding.

[0249] Statistical Analysis: The paired t-test (two-tailed) was used tocompare gastric pH before and after omeprazole solution administrationand to compare gastric pH before omeprazole solution administration withthe mean and lowest gastric pH value measured after beginningomeprazole.

[0250] Results:

[0251] Seventy-seven patients met the inclusion and exclusion criteriaand received omeprazole solution (See FIG. 2). Two patients wereexcluded from the efficacy evaluation because the protocol foromeprazole administration was not followed. In one case, the omeprazoleenteric-coated pellets had not completely broken down prior to theadministration of the first two doses, which produced an erratic effecton gastric pH. The gastric pH increased to above six as soon as thepatient was given a dose of omeprazole solution (in which the entericcoated pellets of omeprazole had been allowed to completely breakdown).

[0252] The reason for the second exclusion was that nasogastricsuctioning was not turned off after the omeprazole dose wasadministered. This resulted in a transient effect on gastric pH. Thesuction was turned off with subsequent omeprazole doses, and control ofgastric pH was achieved. Two patients were considered efficacy failuresbecause omeprazole failed to maintain adequate gastric pH control on thestandard omeprazole 20 mg/day maintenance dose. When the omeprazole dosewas increased to 40 mg/day.(40 mg once/day or 20 mg twice/day), gastricpH was maintained above four in both patients. These two patients wereincluded in the safety and efficacy evaluations, including the gastricpH analysis. After the two patients were declared failures, their pHvalues were no longer followed.

[0253] The ages of the remaining seventy-five patients ranged fromeighteen to eighty-seven years; forty-two patients were male andthirty-three were female. All patients were mechanically ventilatedduring the study. Table 4 shows the frequency of risk factors forstress-related bleeding that were exhibited by the patients in thisstudy. The most common risk factors in this population were mechanicalventilation and major surgery. The range of risk factors for any givenpatient was two to ten, with a mean of 3 (±1) (standard deviation). Fivepatients enrolled in the study had developed clinically significantbleeding while receiving continuous infusions of ranitidine (150 mg/24hr) or cimetidine (900 mg/24 hr). In all five cases, the bleedingsubsided and the gastric pH rose to above five within thirty-six hoursafter initiating omeprazole therapy. Three patients were enrolled afterhaving developed two consecutive gastric pH values below three whilereceiving an H₂-antagonist (in the doses outlined above). In all threecases, gastric pH rose to above five within four hours after omeprazoletherapy was initiated. Four other patients were enrolled in this studyafter experiencing confusion (n=2) or thrombocytopenia (n=2) duringH₂-antigens therapy. Within thirty-six hours of switching therapy, theseadverse events resolved.

[0254] Stress-related Mucosal Bleeding and Mortality: None of thesixty-five patients who received buffered omeprazole solution as theirinitial prophylaxis against stress-related mucosal bleeding developedovert or clinically significant upper gastrointestinal bleeding. In fourof the five patients who had developed upper gastrointestinal bleedingbefore study entry, bleeding diminished to the presence of occult bloodonly (Gastroccult-positive) within eighteen hours of starting omeprazolesolution; bleeding stopped in all patients within thirty-six hours. Theoverall mortality rate in this group of critically ill patients waseleven percent. No death was attributable to upper gastrointestinalbleeding or the use of omeprazole solution.

[0255] Gastric pH: The mean (±standard deviation) pre-omeprazole gastricpH was 3.5±1.9. Within four hours of omeprazole administration, thegastric pH rose to 7.1±1.1 (See FIG. 3); this difference was significant(p<0.001). The differences between pre-omeprazole gastric pH and themean and lowest gastric pH measurements during omeprazole administration(6.8±0.6 and 5.6±1.3, respectively) were also statistically significant(p<0.001).

[0256] Safety: Omeprazole solution was well tolerated in this group ofcritically ill patients. Only one patient with sepsis experienced anadverse event that may have been drug-related thrombocytopenia. However,the platelet count continued to fall after omeprazole was stopped. Theplatelet count then returned to normal despite reinstitution ofomeprazole therapy. Of note, one patient on a jet ventilatorcontinuously expelled all liquids placed in her stomach up and outthrough her mouth, and thus was unable to continue on omeprazole. Noclinically significant drug interactions with omeprazole were notedduring the study period. As stated above, metabolic alkalosis is apotential concern in patients receiving sodium bicarbonate. However, theamount of sodium bicarbonate in omeprazole solution was small (12 mEq/10ml) and no electrolyte abnormalities were found.

[0257] Pneumonia: Pneumonia developed in nine (12%) patients receivingomeprazole solution. Pneumonia was present in an additional fivepatients before the start of omeprazole therapy.

[0258] Pharmacoeconomic evaluation: The average length of treatment wasnine days. The cost of care data are listed in Tables 5 and 6. The costsof drug acquisition, preparation, and delivery for some of thetraditional agents used in the prophylaxis of stress-related uppergastrointestinal bleeding are listed in Table 5. There were no costs toadd from toxicity associated with omeprazole solution. Since two ofseventy-five patients required 40 mg of omeprazole solution daily toadequately control gastric pH, the acquisition/preparation cost shouldreflect this. The additional 20 mg of omeprazole with vehicle adds sevencents per day to the cost of care. Therefore, the daily cost of care foromeprazole solution in the prophylaxis of stress-related mucosalbleeding was $12.60 (See Table 6).

[0259] Omeprazole solution is a safe and effective therapy for theprevention of clinically significant stress-related mucosal bleeding incritical care patients. The contribution of many risk factors tostress-related mucosal damage has been challenged recently. All of thepatients in this study had at least one risk factor that has clearlybeen associated with stress-related mucosal damage—mechanicalventilation. Previous trials and data from a recently published studyshow that stress ulcer prophylaxis is of proven benefit in patients atrisk and, therefore, it was thought to be unethical to include a placebogroup in this study. No clinically significant upper gastrointestinalbleeding occurred during omeprazole solution therapy. Gastric pH wasmaintained above 4 on omeprazole 20 mg/day in seventy-three ofseventy-five patients. No adverse events or drug interaction associatedwith omeprazole were encountered. TABLE 4 Mech Major Head Renal MultipleAcid/ Liver Vent Surgery Multitrauma Injury Hypotension Failure SepsisOperation Base Coma Failure Burn 75 61 35 16 14 14 14 12 10 4 2 2 MechMajor Head Renal Multiple Acid/ Liver Vent Surgery Multitrauma InjuryHypotension Failure Sepsis Operation Base Coma Failure Burn 75 61 35 1614 14 14 12 10 4 2 2

[0260] TABLE 5 Per day RANITIDINE (day 1-9) Rantidine 150 mg/24 hr 6.15Ancillary Product (1) Piggyback (60%) 0.75 Ancillary Product (2) microtubing (etc.) 2.00 Ancillary Product (3) filter 0.40 Sterile Preprequired yes R.N. time ($24/hr) 20 minutes/day (includes pH 8.00monitoring) R.Ph. time, hood maint. 3 minutes ($40/hr) 2.00 Pump cost$29/24 hrs × 50%) 14.50 TOTAL for 9 days 304.20 RANITIDINE Cost per day33.80 CIMETIDINE (day 1-9) Cimetidine 900 mg/24 hr 3.96 AncillaryProduct (1) Piggyback 1.25 Ancillary Product (2) micro tubing (etc.)2.00 Ancillary Product (3) filter 0.40 Sterile Prep required yes 8.00R.N. time ($24/hr) 20 minutes/day (includes pH monitoring) R.Ph. time,hood maint. 3 minutes ($40/hr) 2.00 Pump cost $29/24 hrs × 50%) 14.50TOTAL for 9 days 288.99 CIMETIDINE Cost per day 32.11 SUCRALFATE (day1-9) Sucralfate 1 g × 4 2.40 Ancillary Product (1) syringe 0.20 SterilePrep required no R.N. time ($24/hr) 30 minutes/day (includes pH 12.00monitoring) TOTAL for 9 days 131.40 SUCRALFATE Cost per day 14.60

[0261] TABLE 6 The average length of treatment was 9 days. Cost of carewas calculated from these date Per Day Total OMEPRAZOLE (day 1) Productacquisition cost 40 mg load × 2 (5.66/dose) 11.32 11.32 Ancillaryproduct materials for solution 0.41 0.41 preparation Ancillary productsyringe w/needle 0.20 0.40 Sterile preparation no required 6 minutes2.40 4.80 SOS preparation time 21 minutes/day (includes pH 8.40 8.40(R.N.) monitoring) R.N. time ($24/hr) OMEPRAZOLE (days 2-9) Productacqusition cost 20 mg per day 2.80 22.65 Ancillary product materials forsolution 0.41 0.82 preparation Ancillary product syringe w/needle 0.201.60 Sterile preparation no required 6 minutes 2.40 4.80 SOS preparationtime 18 minutes/day (includes pH 8.40 57.60 (R.N.) monitoring) R.N. time($24/hr) 2/75 patient require 40 mg simplified omeparzole solution perday (days 2-9) No additional cost for adverse effects or for failureTOTAL Simplified Omerprazole Solution cost per day

[0262] TABLE 7 Time Control 1 hour 24 hour 2 day 7 day 14 day Conc(mg/ml) 2.01 2.07 1.94 1.96 1.97 1.98

Example X

[0263] Bacteriostatic and Fungistatic Effects of Omeprazole Solution

[0264] The antimicrobial or bacteriostatic effects of the omeprazolesolution were analyzed by applicant. An omeprazole solution (2 mg/ml of8.4% sodium bicarbonate) made according to the present invention wasstored at room temperature for four weeks and then was analyzed forfungal and bacterial growth. Following four weeks of storage at roomtemperature, no bacterial or fungal growth was detected.

[0265] An omeprazole solution (2 mg/ml of 8.4% sodium bicarbonate) madein accordance with the present invention was stored at room temperaturefor twelve weeks and then was analyzed for fungal and bacterial growth.After twelve weeks of incubation at room temperature, no fungal orbacterial growth was detected.

[0266] The results of these experiments illustrate the bacteriostaticand fungistatic characteristics of the omeprazole solution of thepresent invention.

Example XI

[0267] A. Bioequivalency Study.

[0268] Healthy male and female study participants over the age of 18will be randomized to receive omeprazole in the following forms:

[0269] (A) 20 mg of a liquid formulation of approximately 20 mgomeprazole in 4.8 mEq sodium bicarbonate qs to 10 ml with water;

[0270] (B) 20 mg of a liquid formulation of approximately 2 mgomeprazole per 1 ml of 8.4% sodium bicarbonate.

[0271] (C) Prilosec® (omeprazole) 20 mg capsule;

[0272] (D) Capsule prepared by inserting non-enteric coated omeprazole20 mg into a #4 empty gelatin capsule (Lilly) uniformly dispersed in 240mg of sodium bicarbonate powder USP to form an inner capsule. The innercapsule is then inserted into a #00 empty gelatin capsule (Lilly)together with a homogeneous mixture of 600 mg sodium bicarbonate USP and110 mg pregelatinized starch NF.

[0273] After appropriate screening and consent, healthy volunteers willbe randomized to receive one of the following four regimens as randomlyassigned by Latin Square. Each subject will be crossed to each regimenaccording to the randomization sequence until all subjects have receivedall four regimens (with one week separating each regimen).

[0274] Regimen A (20 mg omeprazole in 4.8 mEq sodium bicarbonate in 10ml volume); Regimen B (20 mg omeprazole in 10 ml 8.4% sodium bicarbonatein 10 ml volume); Regimen C (an intact 20 mg omeprazole capsule);Regimen D (Capsule in capsule formulation, see above). For eachdose/week, subjects will have an i.v. saline lock placed for bloodsampling. For each regimen, blood samples will be taken over 24 hours atotal of 16 times (with the last two specimens obtained 12 hours and 24hours after drug administration).

[0275] B. Patient Eligibility

[0276] Four healthy females and four healthy males will be consented forthe study.

[0277] C. Inclusion Criteria

[0278] Signed informed consent.

[0279] D. Exclusion Criteria

[0280] 1. Currently taking H₂-receptor antagonist, antacid, orsucralfate.

[0281] 2. Recent (within 7 days) therapy with lansoprazole, omeprazole,or other proton pump inhibitor.

[0282] 3. Recent (within 7 days) therapy with warfarin.

[0283] 4. History of variceal bleeding.

[0284] 5. History of peptic ulcer disease or currently active G.I.bleed.

[0285] 6. History of vagotomy or pyloroplasty.

[0286] 7. Patient has received an investigational drug within 30 days.

[0287] 8. Treatment with ketoconazole or itraconazole.

[0288] 9. Patient has an allergy to omeprazole.

[0289] E. Pharmocokinetic Evaluation and Statistical Analysis

[0290] Blood samples will be centrifuged within 2 hours of collectionand the plasma will then separated and frozen at −100° C. (or lower)until assayed. Pharmacokinetic variables will include: time to peakconcentration, mean peak concentration, AUC (0-t) and (0-infinity).Analysis of variance will be used to detect statistical difference.Bioavailability will be assessed by the 90% confidence interval of thetwo one-sided tests on the natural logarithm of AUC.

[0291] F. HPLC Analysis

[0292] Omeprazole and internal standard (H168/24) will be used.Omeprazole and internal standard will be measured by modification of theprocedure described by Amantea and Narang. (Amantea M A, Narang P K.Improved Procedure for Quantification of Omeprazole and MetabolitesUsing Reversed-Phased High Performance Liquid Chromotography. J.CHROMATOGRAPHY 426; 216-222 (1988)). Briefly, 20 ul of omeprazole 2mg/ml NaHCO₃ or Choco-Base omeprazole suspension and 100ul of theinternal standard are vortexed with 150 ul of carbonate buffer (pH-9.8),5 ml of dichloroethane, 5 ml of hexane, and 980 ul of sterile water.After the sample is centrifuged, the organic layer is extracted anddried over a nitrogen stream. Each pellet is reconstituted with 150 ulof mobile phase (40% methanol, 52% 0.025 phosphate buffer, 8%acetonitrile, pH=7.4). Of the reconstituted sample, 75 ul is injectedonto a C₁₈5 U column equilibrated with the same mobile phase at 1.1ml/min. Under these conditions, omeprazole is eluted at approximately 5minutes, and the internal standard at approximately 7.5 minutes. Thestandard curve is linear over the concentration range 0-3 mg/ml (inprevious work with SOS), and the between-day coefficient of variationhas been <8% at all concentrations. The typical mean R² for the standardcurve has been 0.98 in prior work with SOS (omeprazole 2 mg/ml NaHCO₃8.4%).

[0293] Applicant expects that the above experiments will demonstratethere is more rapid absorption of formulations (a), (b) and (d) ascompared to the enteric coated granules of formulation (c).Additionally, applicant expects that although there will be a differencein the rates of absorption among forms. (a) through (d), the extent ofabsorption (as measured by the area under the curve (AUC)) should besimilar among the formulations (a) through (d).

Example XII

[0294] Intraveneous Proton Pump Inhibitor in Combination With OralParietal Cell Activator.

[0295] Sixteen (16) normal, healthy male and female study subjects overthe age of 18 will be randomized to receive pantoprazole as follows:

[0296] (a) 40 mg IV over 15 to 30 minutes in combination with a 20 mloral dose of sodium bicarbonate 8.4%; and

[0297] (b) 40 mg IV over 15 to 30 minutes in combination with a 20 mloral dose of water.

[0298] The subjects will receive a single dose of (a) or (b) above, andwill be crossed-over to (a) and (b) in random fashion. Serumconcentrations of pantoprazole versus time after administration datawill be collected, as well as gastric pH control as measured with anindwelling pH probe.

[0299] Further, similar studies are contemplated wherein chocolate orother parietal cell activator is substituted for the parietal cellactivator sodium bicarbonate, and other proton pump inhibiting agentsare substituted for pantoprazole. The parietal cell activator can beadministered either within about 5 minutes before, during or withinabout 5 minutes after the IV dose of proton pump inhibitor.

[0300] Applicant expects that these studies will demonstrate thatsignificantly less IV proton pump inhibitor is required to achievetherapeutic effect when it is given in combination with an oral parietalcell activator.

[0301] Additionally, administration kits of IV proton pump inhibitor andoral parietal cell activator can be packaged in many various forms forease of administration and to optimize packing and shipping the product.Such kits can be in unit dose or multiple dose form.

Example XIII

[0302] Six (6) Month Stability of Omeprazole Suspension.

[0303] A suspension was prepared by mixing 8.4% sodium bicarbonate withomeprazole to produce a final concentration of 2 mg/ml to determine thestability of omeprazole solution after 6 months. The resultantpreparation was stored in clear glass at room temperature, refrigeratedand frozen. Samples were drawn after thorough agitation from the storedpreparations at the prescribed times. The samples were then stored at70° C. Frozen samples remained frozen until they were analyzed. When thecollection process was completed, the samples were shipped to alaboratory overnight on dry ice for analysis. Samples were agitated for30 seconds and sample aliquots were analyzed by HPLC in triplicateaccording to well known methods. Omeprazole and the internal standardwere measured by a modification of the procedure described by Amanteaand Narang. (Amantea M A, Narang P K, Improved Procedure ForQuantitation Of Omeprazole And Metabolites Using Reverse-PhasedHigh-Performance Liquid Chromatography, J. CHROMATOGRAPHY, 426: 216-222(1988)). Twenty (20) ul of the omeprazole 2 mg/ml NaHCO₃ solution and100 ul of the internal standard solution were vortexed with 150 ul ofcarbonate buffer (pH=9.8), 5 ml dichloroethane, 5 ml hexane, and 980 ulof sterile water. The sample was centrifuged and the organic layer wasextracted and dried over a nitrogen stream. Each pellet wasreconstituted with 150 ul of mobile phase (40% methanol, 52% 0.025phosphate buffer, 8% acetonitrile, pH=7.4). Of the reconstituted sample,75 ul were injected onto a C185u column equilibrated with the samemobile phase at 1.1 ml/min. Omeprazole was eluted at ˜5 min, and theinternal standard at ˜7.5 min. The standard curve was linear over theconcentrated range 0-3 mg/ml, and between-day coefficient of variationwas <8% at all concentrations. Mean R² for the standard curve was 0.980.

[0304] The 6 month sample showed stability at greater than 90% of theoriginal concentration of 2 mg/ml. (i.e., 1.88 mg/ml, 1.94 mg/ml, 1.92mg/ml).

Example XIV

[0305] Pharmacokinetic and Pharmacodynamic Study of Duodenal or JejunalAdministration Compared to Nasogastric Administration of OmeprazoleSuspension in Patients at Risk for Stress Ulcers

[0306] Omeprazole suspension administered by the jejunal or duodenalroute was compared in a randomized, cross-over fashion with nasogastricadministration in patients at risk for stress related GI bleeding.Eligible for study enrollment were all adult patients (>18 yr.) admittedto the surgical intensive care unit who had recently undergone a majorsurgical procedure or were. posttrauma with an Acute Physiological andChronic Health Evaluation (APACHE II) score >18. To be included in thestudy, patients were also required to be mechanically ventilated inaddition to having at least one of the following risk factors: headinjury with altered level of consciousness; extensive burns (>20% bodysurface area); acute renal failure; acid-base disorder; multipletraumas; coagulopathy; multiple operative procedures; coma; hypotensionfor >1 h; or sepsis syndrome. Patients were excluded from participationif they had any of the following characteristics: hypochlorhydria;status of “Do Not Resuscitate”; a history of vagotomy, pyloroplasty, orgastroplasty; an allergy to proton pump inhibitors; active GI bleeding(including variceal bleeding); thrombocytopenia (<30,000/mm³ platelets);active peptic ulcer disease treated within the past year; were likely atrisk of swallowing blood (i.e., severe facial trauma, oral lacerations,hemoptysis); currently or during the study receiving ketoconazole oritraconazole or enteral tube feedings; or had received aninvestigational drug within 30 days, omeprazole or another proton pumpinhibitor within 5 days, or warfarin or nonsteroidal anti-inflammatorydrugs (NSAIDs), including aspirin, within 24 h. Administration of thestudy drug was not initiated until the patient had documented gastric pHof <4.0. If 48 h had passed and gastric pH was not <4.0, the patient wasexcluded from study participation. Patients who were on prior acidreducing therapy for <24 h were allowed to participate afterdiscontinuation of their medication and gastric acidity achieved thestudy-imposed pH range (gastric pH<4.0). Subjects were not allowed toreceive antisecretory agents (e.g., H2RA) during the study. Theinstitutional Review Board for the University of Missouri at Columbiaapproved the protocol and informed consent was obtained before studyenrollment for every subject.

[0307] Omeprazole suspension was compounded and stored in amber bottlesat 4° C. The omeprazole was prepared by dissolving the contents of two20-mg capsules (Prilosec®, Astra-Zeneca, Wayne, Pa.) in 20 ml of 8.4%sodium bicarbonate (Abbott Laboratories, North Chicago, Ill.) withgentle shaking to assure adequate mixing. The sodium bicarbonatedissolves the enteric-coated beads leaving “free omeprazole” in thesuspension.

[0308] A nasogastric tube and needle catheter jejunostomy or duodenaltube was placed before study initiation. Placement of the nasogastrictube was confirmed by x-ray and aspiration of gastric contents for pHconfirmation. The jejunostomy and duodenal tubes were placed by standardsurgical technique and positioning was confirmed by x-ray. On study day1, when gastric pH decreased to <4, the patients were randomized toreceive a single 40 mg dose of omeprazole suspension by eithernasogastric tube or jejunal/duodenal administration. When gastric pHsubsequently dropped again to <4 (>24 h in all patients), each patientwas crossed-over to the other administration route followed by a single40 mg dose of omeprazole suspension. All patients received thecross-over dose 72 h after the first day and after the pH had dropped to<4. After omeprazole administration, the nasogastric or duodenal/jejunaltube was flushed with 10 ml of water and clamped for 1-2 h. A Latinsquare cross-over design was used.

[0309] A total of 60 ml of blood was collected in 2.5 ml aliquots over aperiod of 24 h to establish the absorption and pharmacokineticparameters of omeprazole as administered by the different enteralroutes. Blood samples were obtained immediately before each dose of drugand at 3, 5, 10, 20, 30, 60, 120, 240, 480, 720, 960, and 1440 min afterdrug administration. All samples were collected in red-top tubes(Vacutainer®, Becton-Dickinson, Franklin Lakes, N.J.), allowed to clotfor 30 min at room temperature, and centrifuged for 10 minutes at 1000g. The resulting sera was removed and immediately frozen at −70° C.until analysis. The study was conducted for approximately 4 days perpatient.

[0310] Continuous monitoring of gastric acidity (pH) occurred throughoutthe study period for all patients who received omeprazole suspension.Continuous gastric pH readings were measured with a Zinetics probe(Zinetics Medical, Salt Lake City, Utah).

[0311] Omeprazole plasma concentrations were determined by modificationof a previously published high-performance liquid chromatography assay.The range of linearity for the assay was 25-1000 ng/ml for serum. Thelower limits of detection were 10 ng/ml. Coefficients of variation (R²)for the omeprazole assay over the standard curve concentrationswere >0.99 for the entire study. Intra- and interassay coefficients ofvariation were consistently <8.5% at concentrations included in thelinearity range.

[0312] The serum omeprazole concentration-time data were analyzed viaWinNonlin Software, Standard Edition, Version 1.5 (ScientificConsulting, Cary, N.C.). First dose pharmacokinetic parameters includinghalf-life (T_(1/2)), maximum serum-concentration (C_(max)), time tomaximum serum concentration (T_(max)), drug clearance (C1_(ss)/F) wereestimated using a noncompartmental extravascular dose model. Area underthe serum-concentration time curve (AUC) was determined by trapezoidalrule and was extrapolated to 24 h (AUC₀₋₂₄) and to infinity (AUC₀₋₀₀),using the fitted values of the final plasma concentration time curves.

[0313] Demographic, pH, and pharmacokinetic data are reported as themean ±SD as well as the range for respective values when appropriate.The pharmacodynamic relationship between various pharmacokineticparameters, including clearance (C1 and AUC, were compared to mean pHvalues obtained for each respective administration route and analyzed bylinear regression. Omeprazole concentrations-time data, graphicalrepresentation, and statistical analysis were performed with Prismsoftware (GraphPad, Chicago, Ill.). Ap value of <0.05 was consideredsignificant for all statistical analyses.

[0314] Omeprazole absorption and pharmacokinetic analyses were performedin nine critically ill surgical patients (five men and four women). Theadministration was well tolerated without any apparent adverse events.The mean (±SD) age, weight, and creatinine clearance of these patientswere 33±11 yr (range, 23-56 yr), 78±19 kg (range, 59-124 kg), and95±24.0 ml/min (range, 35-120 ml/min), respectively. No patients haddemonstrated liver disease by either clinical or laboratory evidence ofhepatic dysfunction. All nine patients received omeprazole vianasogastric administration, compared with seven and two patients whowere also randomized to receive the drug via the jejunal or duodenalroute, respectively. Pharmacokinetic parameters for both groups areshown in Table 8. The mean plasma concentration-time curves after 40 mgof omeprazole suspension administered via the nasogastric andjejunal/duodenal routes produced a biphasic curve with the higher peakserum concentrations resulting from the jejunal/duodenal group comparedto nasogastric administration (1.833±0.416 μg/m vs. 0.970±0.436 ,μg/ml,p=0.006). Omeprazole absorption was also significantly slower bycomparison of time to maximum concentration (T_(max)) when administeredby nasogastric tube vs. jejunal/duodenal administration (108.3±42.0 vs.12.1±7.9 min. p<0.0001). Other mean pharmacokinetic parameters (t_(1/2),C1_(ss), AUC₀₋₂₄, AUC₀₋₀₀) were not statistically different between thetwo groups, although there was a trend toward a shorter half-life forpatients who received drug via the jejunal/duodenal route.

[0315] The mean baseline pH was 1.63±0.89 for the jejunal/duodenal groupand 2.12±0.67 for the nasogastric group (p=0.26). Mean intragastric pHvalues rose to >41 h after omeprazole administration and remained >4 forthe entire 24-h study period in both groups. When comparing the mean pHdata (nasogastric (6.32±1.04) vs. jejunal/duodenal (5.57±1.15), p=0.015)nasogastric administration maintained higher gastric pH valuesthroughout the study with fewer incidences of pH values <4.0 overall.TABLE 8 Pharmacokinetic Parameters of Omeprazole Suspension NasogastricJejunal/Duodenal p Variable (N = 9) (N = 9) Value AUC₀₋₂₄ 373.3 ± 256.2375.3 ± 340.1 0.99 AUC₀₋₀₀ 415.1 ± 291.8 396.7 ± 388.1 0.91 T_(max)(min) 108.3 ± 42.0  12.1 ± 7.9 <0.001 T_(1/2) (min) 250.7 ± 100.0 162.9± 138.9 0.14 C1/F 0.144 ± 0.098 0.199 ± 0.137 0.34 C_(max) (μg/ml) 0.970± 0.436 1.833 ± 0.416 0.0006

[0316] In summary, nasogastric administration of SOS resulted in lowermaximum mean±SD serum concentrations compared to jejunal/duodenal dosing(0.970±0.436 vs. 1.833±0.416 μg/ml, p=0.006). SOS absorption wassignificantly slower when administered via nasogastric tube (108.3±42.0vs. 12.1±7.9 min, p<0.001). However, all routes of administrationresulted in similar SOS area under the serum concentration-time curves(AUC₀₋₀₀) (415.1±291.8 vs. 396.7±388.1 μg h/ml, p=0.91). Meanintragastric pH values remained >4 at 1 h after SOS administration andremained >4 for the entire 24-h study (nasogastric (6.32±1.04) vs.jejunal/duodenal (5.57±1.15), p=0.015), regardless of administrationroute.

Example XV

[0317] Simplified Omeprazole Suspension (SOS)pharmacokinetic/pharmacodynamic study in patients at risk forstress-related mucosal damage (SRMD).

[0318] A. Protocol

[0319] Hospitalized patients who were at risk of stress-related mucosaldamage (SRMD) were enrolled in this study to evaluate the serumconcentration vs. time profile and intragastric pH changes accompanyinga single dose of omeprazole 40 mg in 20 mEq sodium bicarbonatesuspension. Patients at risk for SRMD were considered eligible andreceived no prior treatment with omeprazole (within 5 days). InformedConsent was obtained. A nasogastric tube (with a pH probe—incorporatedin the tip—GraphProbe ZineticsMedical) was placed in the stomach bystandard means. Patients received a dose of SOS (40 mg omeprazole in 20mL 8.4% sodium bicarbonate) after the gastric pH dropped below 4. Serumconcentrations of omeprazole were drawn at the following times:  0 min 3 min 5 min 10 min 15 min 20 min 30 min 45 min 1 hr  2 hrs  4 hrs  8hrs 12 hrs 24 hrs

[0320] Gastric pH tracings were made using the ZineticsMedicalGraphProbe and the DataLogger from Sandhill scientific.

[0321] Serum was ultracentrifuged and stored at −70° C. and sent as asingle batch to David Flockhart MD, PhD at Georgetown University MedicalCenter for HPLC (High Pressure Liquid Chromatography) measurement.

[0322] B. Results

[0323] The omeprazole plasma concentrations for 17 subjects are providedbelow in Table Nos. 12, 13, 14, and 15. Below is also a summary thepharmacokinetic and pharmacodynamic findings.

[0324] 1. Pharmacokinetic

[0325] Absorption: Absorption was rapid as indicated by the appearanceof omeprazole in serum at <10 minutes in many subjects.

[0326] Tmax: The C max (maximum serum concentration) was also rapidlyattained when compared to the enteric-coated granules. The C max in mostevery patient appearing before 1 hour (Tmax).

[0327] AUC: The absorption of the omeprazole did not appear to besignificantly decreased when compared to omeprazole in theenteric-coated form as measured by Area Under the Curve (AUC).

[0328] 2. Pharmacodynamic

[0329] The gastric pH control appeared to be very rapid and sustained atan unusually high pH for a first dose of omeprazole. TABLE 9 OmeprazoleConcentrations Over time for Patient Nos. 1-5 (μg/ml) Patient #1 Patient#2 Patient #3 Patient #4 Patient #5 [Omeprazole] [Omeprazole][Omeprazole] [Omeprazole] [Omeprazole] Time μg/ml plasma μg/ml plasmaμg/ml plasma μg/ml plasma μg/ml plasma  1 min. ND ND ND ND ND  3 min. ND0.155 0.149 0.02 ND  5 min. 0.201 0.44 0.165 0.148 0.1 10 min. 0.3220.551 0.233 0.34 0.278 15 min. ND 0.587 0.261 0.44 0.413 20 min. 0.3811.01 0.382 0.554 0.537 30 min. 0.445 1.33 0.386 0.718 0.628 45 min.0.658 1.46 0.445 0.89 0.68  1 hr. 0.755 1.24 0.501 0.893 0.749  2 hrs.0.911 0.894 0.715 0.695 0.763  4 hrs. 0.976 0.13 0.463 ND 0.622  8 hrs.0.78 0.05 0.305 ND 0.319 12 hrs. 0.303 ND 0.293 ND 0.133 18 hrs. ND NDND ND ND 24 hrs. 0.218 ND 0.215 ND ND

[0330] TABLE 10 Omeprazole Concentrations Over time for Patient Nos.6-10 (μg/ml) Patient #6 Patient #7 Patient #8 Patient #9 Patient #10[Omeprazole] [Omeprazole] [Omeprazole] [Omeprazole] [Omeprazole] Timeμg/ml plasma μg/ml plasma μg/ml plasma μg/ml plasma μg/ml plasma  1 min.ND ND ND ND ND  3 min. ND ND ND ND 0.041  5 min. ND 0.756 0.291 0.0440.058 10 min. 0.067 1.15 0.316 0.0525 0.117 15 min. 0.072 0.95 0.340.073 0.192 20 min. 0.05 ND 0.44 0.096 0.213 30 min. 0.0925 ND 0.660.152 0.237 45 min. 0.095 ND 0.437 0.186 0.234  1 hr. 0.058 0.623 0.3860.24 0.263  1 hr. 15 min. ND 0.61 ND ND ND  2 hrs. 0.012 0.177 0.1530.406 0.221  4 hrs. ND 0.107 0.044 0.865 0.391  8 hrs. ND ND ND 0.3030.164 12 hrs. ND ND ND 0.168 0.055 18 hrs. ND ND ND ND ND 24 hrs. ND NDND 0.108 ND

[0331] TABLE 11 Omeprazole Concentrations Over time for Patient Nos. 1-5(μg/ml) Patient #1 Patient #2 Patient #3 Patient #4 Patient #5[Omeprazole] [Omeprazole] [Omeprazole] [Omeprazole] [Omeprazole] Timeμg/ml plasma μg/ml plasma μg/ml plasma μg/ml plasma μg/ml plasma  1 min.ND ND ND ND ND  3 min. 0.0275 ND ND ND ND  5 min. 0.0735 ND ND ND 0.1075(or 20 min.) 10 min. 0.131 ND 1.12 0.131 0.155 15 min. 0.154 ND 1.080.161 0.176 17 min. ND ND ND ND ND 20 min. 0.177 0.012 1.04 0.187 ND (or5 min.) 30 min. 0.388 0.025 0.865 0.224 0.184 45 min. 0.526 0.046 0.8410.269 0.196  1 hr. 0.486 0.077 0.896 0.276 0.155  2 hrs. 0.458 0.1280.504 0.343 0.17  4 hrs. 0.466 0.17 0.278 0.435 0.139  8 hrs. 0.2320.148 0.145 0.204 ND 12 hrs. 0.093 0.052 ND 0.131 ND 18 hrs. ND ND ND NDND 24 hrs. ND ND ND ND ND

[0332] TABLE 12 Omeprazole Concentrations Over time for Patient Nos.16-17 (μg/ml) Patient #16 Patient #17 [Omeprazole] [Omeprazole] Timeμg/ml plasma μg/ml plasma  1 min. ND ND  3 min. ND ND  5 min. ND ND 10min. ND 0.504 15 min. ND 0.6932 20 min. ND 0.765 30 min. 0.076 0.777 45min. 0.186 0.645  1 hr. 0.242 0.547  2 hrs. 0.193 0.508  4 hrs. ND ND  8hrs. ND ND 12 hrs. ND ND 18 hrs. ND ND 24 hrs. ND ND

Example XVI

[0333] A Comparison of the Pharmacokinetics and Pharmacodynamics ofOmeprazole Delivered Orally with Different Doses of Antacid in FastedSubjects

[0334] A. Administration of Test Articles

[0335] Test articles were administered to each subject according to thefollowing schedule:

[0336] Period 1: 1 antacid tablet (30 mEq of 1 part sodium bicarbonateto 3 parts calcium carbonate) plus 40 mg omeprazole powder wasadministered in the fasted state with 60 mL (2 oz.) water.

[0337] Period 2: A solution/suspension of omeprazole 40 mg and 20 mEq ofsodium bicarbonate (total volume 20 mL in an amber bottle) wasadministered to the subject. Immediately (within 30 seconds) afteradministration, the bottle was rinsed with a small amount of water,which was also administered to the subject. The rinse step was repeatedand the subject was given a total of 100 mL of water after theadministration of the 20 mL of the omeprazole/sodium bicarbonatesolution/suspension.

[0338] Period 3: 1 capsule of Prilosec (40 mg of enteric-coatedomeprazole alone) in the fasted state with 120 mL water.

[0339] Period 5: 1 antacid tablet (30 mEq of 1 part sodium bicarbonateto 1 part calcium carbonate) plus 40 mg omeprazole powder wasadministered in the fasted state with 120 ml water.

[0340] B. Treatment Periods

[0341] Only 1 day (Day 1) was required in the clinic. Subjects fastedfor at least 10 hours overnight in the clinic prior to initiating pHmonitoring; they were allowed water ad libitum until 1 hour prior todose administration.

[0342] Each subject receiving 40 mg of omeprazole powder wasadministered the drug product by site staff directly onto the dorsalmid-tongue. Immediately thereafter, subjects were administered one ortwo chewable antacid tablets and began chewing. Each subject continuedto chew the tablet(s), while mixing it with the omeprazole powder,carefully avoiding swallowing the powder immediately. One minute afterinitiating chewing (and after completely swallowing the test articles),each subject drank 60-120 mL of water rising the oral cavity beforeswallowing. No additional water was allowed until after the 6-hourpostdose pH and blood samples were taken. Water was allowed ad libitum.For pharmacokinetic/pharmacodynamic sampling, zero time was the timethat chewing is initiated.

[0343] C. Inclusion Criteria

[0344] Subjects were included in the trial if they met all of thefollowing:

[0345] 1. Were non-Asian males from 18 to 45 years of age.

[0346] 2. Were within the ranges of about 20% of ideal body weight.

[0347] 3. Were in good health on the basis of history, physicalexamination, and laboratory values.

[0348] 4. Had not used any form of tobacco (e.g., smoking, chewing) forthe last year.

[0349] 5. Tolerated installation of nasogastric pH probe for at least 5minutes.

[0350] 6. Had a basal gastric pH at each trial visit of less than 2.5.

[0351] D. Exclusion Criteria

[0352] Subjects were excluded from the trial if they met any of thefollowing:

[0353] 1. Had a significant history of/or concurrent gastrointestinaldisease or condition, such as GERD, heartburn, reflux esophagitis,peptic ulcer disease (gastric or duodenal), or a family history ofpeptic ulcer disease, gastric surgery (e.g., vagotomy, pyloroplasty).

[0354] 2. Had any significant medical history or concurrent illness,such as respiratory, allergic, psychiatric, neurological, renal,hepatic, cardiovascular, metabolic, or endocrine condition, or any othermedical condition which the investigator or medical monitor consideredsufficiently serious to interfere with the conduct, completion, orresults of the trial, or constituted an unacceptable risk to thesubject.

[0355] 3. Had a history of significant drug allergy.

[0356] 4. Known hypersensitivity to any of the ingredients in the testarticles.

[0357] 5. Had a positive urine test of alcohol or other drugs at anytrial visit.

[0358] 6. Had taken any gastric antisecretory drugs, e.g.,. H2antagonists or PPIs, or antacids (including OTC medications) within 14days prior to Period 1 or during the trial.

[0359] 7. Had taken xanthine-containing foods or beverages (e.g.,coffee, tea, chocolate) within 48 hours of entering the clinic for eachtrial period.

[0360] 8. Had ingested grapefruit juice within 7 days of doseadministration in any trial period.

[0361] 9. Had donated blood within 90 days of entering the trial.

[0362] 10. Had been treated with any investigational drug or therapy, orparticipated in a clinical trial in the 90 days prior to entering thetrial.

[0363] 11. Had any condition which could have interferes withassessments, posed additional risks in administration of the trial drugto the subject, or precluded completion of the trial, including ahistory of noncompliance, alcoholism, or drug abuse.

[0364] 12. Had any laboratory test results deviating from the normalreference ranges established by the local laboratory by more then 20%that the investigator judged to be of possible clinical significance.

[0365] 13. Evidence of infection with HIV.

[0366] 14. Known carrier of hepatitis B surface antigen.

[0367] 15. Known carrier of hepatitis C antibody.

[0368] E. Omeprazole Pharmacokinetics

[0369] Blood samples (10 mL) for measurement of plasma omeprazole weretaken within 30 minutes prior to each dosing, and at 5, 10, 15, 30, 45,60, 90, 120, 180, 240, 300, and 360 minutes (6 hours) after dosing.These samples were taken at the same time as the gastric pH was beingrecorded. Plasma omeprazole was measured using a previously validatedLC-MSMS assay. Zero time was the time that the subject first chewed atable formulation, swallowed a capsule, or first swallowed a liquidformulation of test article.

[0370] F. Test Article Evaluation (Day 1)

[0371] On Day 1, after a greater than or less than 10 hour fast, pHrecordings of the gastric fluid began in the morning for 1 hour prior todosing. The pH monitoring continued for 6 hours postdose.

[0372] G. Pharmacokinetic Analysis of Omeprazole

[0373] The following pharmacokinetic parameters were evaluated:

[0374] Omeprazole plasma concentration at each sampling time.

[0375] Peak omeprazole plasma concentration (C_(max)) and time to peakplasma concentration (T_(max)) obtained directly from the data withoutinterpolation.

[0376] Terminal elimination rate constant (k_(el)) determined from alog-linear regression analysis of the terminal plasma omeprazoleconcentrations.

[0377] Terminal elimination half-life (t_(1/2)) calculated as0.693/k_(el).

[0378] Area under the omeprazole plasma concentration-time curve fromtime zero to time “t” (AUC_(0-t)), calculated using the trapezodial rulewith the plasma concentration at time “t” being the last measurableconcentration.

[0379] Area under the omeprazole plasma concentration-time curve fromtime zero to time infinity (AU_(0-inf)), calculated asAUC_(0-t)+C_(t)/k_(el), where C_(t) is the last measurable plasmaconcentration and k_(el) is the terminal elimination rate constantdefined above.

[0380] H. Onset, Duration, and Magnitude of Effects

[0381] Onset of action was defined as the earliest time that the valuewith active treatment was significantly different from the correspondingbaseline value. The baseline value for each subject was the mean ofvalues from the twelve 5-minute baseline periods.

[0382] Duration of action was the latest time that the value with activetreatment was significantly different from the corresponding baselinevalue.

[0383] Magnitude of effect was evaluated for each 5-minute postdosinginterval as well as for the postdosing intervals 0-360 minutes.

[0384] I. Description

[0385] The chewable antacid tablets were produced by MurtyPharmaceuticals, Inc. (518 Codell Drive, Lexington, Ky. 40509-1016) andcontained sodium bicarbonate and calcium carbonate, as well as commonexcipients.: Additional formulation(s) for oral administration and maycontain sodium bicarbonate and/or calcium carbonate either as a tabletor liquid, in addition to omeprazole. USP grade, bulk omeprazole waspurchased from Esteve Quimica, S. A. (Barcelona, Spain).

[0386] At the trial site, the pharmacy staff mixed omeprazole powderwith powdered peppermint flavoring and Equal® Sweetener (containingaspartame) [1 part omeprazole: 2 parts peppermint flavoring: 1.8 partEqual®]. For each unit dose, 120 mg (containing 40 mg omeprazole powder)was weighed on an analytic balance within 1-2 hours of doseadministration in each time period. This mixture was stored undercontrolled conditions of humidity and temperature.

[0387] J. Results

[0388] The omeprazole plasma concentrations for 10 subjects of the studyare provided below in Table No. 13. TABLE 13 Omeprazole Concentrations(ng/ml) Sub Sampling Times (hour) No. Period 0.00 0.08 0.17 0.25 0.500.75 1.00 1.50 2.00 3.00 4.00 5.00 6.00 1 1 0.00 16.4 321 738 968 783605 357 211 97.9 40.1 16.9 11.4 1 2 0.00 79.3 312 388 441 454 292 200128 43.4 21.0 9.44 4.32 1 3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 39.4 120366 406 161 109 1 5 NS NS NS NS NS NS NS NS NS NS NS NS NS 2 1 0.00 6.82234 326 582 875 615 322 220 84.2 38.1 14.7 6.39 2 2 0.00 47.6 84.3 1681040 717 484 265 162 67.6 26.2 11.6 4.02 2 3 0.00 0.00 0.00 0.00 1.5751.3 98.6 363 379 429 204 99.0 51.2 2 5 0.00 22.9 315 661 983 797 582375 306 124 57.8 25.3 12.2 3 1 0.00 203 1230 1450 1000 693 525 306 19179.3 32.2 14.8 7.22 3 2 0.00 20.6 302 583 831 740 573 336 203 82.0 37.617.6 9.38 3 3 0.00 0.00 0.00 0.00 9.85 57.7 179 683 681 345 158 85.445.9 3 5 NS NS NS NS NS NS NS NS NS NS NS NS NS 4 1 0.00 4.57 164 5161230 780 495 254 153 55.0 20.8 8.52 3.93 4 2 0.00 9.53 61.6 471 881 566388 182 107 36.5 17.9 6.17 2.63 4 3 0.00 0.00 0.00 0.00 0.00 0.00 18.6386 454 233 126 81.3 51.7 4 5 0.00 196 1240 1740 994 644 493 305 207 10144.3 18.9 8.16 5 1 0.00 107 984 1080 662 409 250 118 60.3 19.7 7.44 2.951.47 5 2 0.00 385 1400 1380 693 394 278 144 78.1 21.8 7.20 2.16 BQL 5 30.00 0.00 0.00 BQL 9.25 44.0 319 340 252 95.5 38.8 14.6 8.16 5 5 0.0088.9 1210 1120 677 430 325 173 97.8 35.1 13.4 5.04 2.06 6 1 0.00 32.8349 552 648 425 267 133 68.4 24.7 9.90 4.21 2.72 6 2 0.00 13.0 68.8 101469 349 241 212 104 31.8 9.31 3.17 1.16 6 3 0.00 0.00 0.00 0.00 24.0 234588 351 162 85.0 29.0 14.4 5.59 6 5 0.00 5.72 26.6 50.2 190 514 398 177108 51.3 22.0 7.75 3.45 7 1 0.00 5.24 97.4 269 638 543 431 255 164 63.629.0 11.9 5.79 7 2 0.00 84.0 960 1170 899 543 433 231 140 54.1 24.0 12.05.54 7 3 0.00 0.00 0.00 5.42 31.0 992 1110 515 310 115 47.0 21.8 9.32 75 0.00 5.35 72.9 165 363 302 221 268 256 150 71.1 29.4 11.4 8 1 0.0049.9 358 746 1090 784 609 367 243 104 51.1 23.1 12.1 8 2 0.00 38.6 2621280 846 563 434 237 148 66.9 29.5 15.7 6.15 8 3 0.00 0.00 0.00 0.000.00 3.84 80.6 401 313 476 225 108 47.1 8 5 0.00 19.7 148 582 1130 822688 461 264 132 64.5 31.8 15.8 9 1 0.00 16.0 139 309 462 355 330 605 317111 47.2 21.9 10.2 9 2 0.00 277 1550 1740 1150 744 522 305 178 79.2 36.614.1 6.96 9 3 0.00 0.00 0.00 0.00 0.00 1.62 47.7 551 566 287 153 98.052.5 9 5 NS NS NS NS NS NS NS NS NS NS NS NS NS 10 1 0.00 15.8 130 202311 233 456 378 187 61.6 21.2 9.90 4.20 10 2 0.00 250 1010 1100 634 421310 136 80.7 28.5 11.6 4.85 1.87 10 3 0.00 0.00 0.00 0.00 5.80 114 148366 390 174 79.4 29.2 10.5 10 5 0.00 103 994 1190 702 562 353 198 11036.7 14.3 5.40 2.28

[0389] VI. Proton Pump Inhibitor Compositions and Method for Optimizingthe Buffer to be Administered in Combination With a Proton PumpInhibitor

[0390] A. Introduction

[0391] The compositions of the present invention are designed to producerapid release of active drug to the site of delivery (typically thestomach) without the necessity of enteric coatings or delayed releaseddosage forms, while preventing acid degradation of the drug. Acid labileproton pump inhibiting agents, for example, can be formulated orcoadministered with one or more buffers sufficient to protect the protonpump inhibitor in any environment, with the ultimate goal being todeliver a proton pump inhibitor to the stomach (or other environment)either via a liquid, a powder or solid dosage form that produces animmediate release of active drug to the site of delivery such that theproton pump inhibitor is quickly available for absorption. Accordingly,Applicant has found that certain amounts of buffers coadministered ormixed with certain proton pump inhibiting agents prevent aciddegradation of the proton pump inhibitor when the buffers produce a pHin the stomach or other site of environment that is equal to the pKa ofthe proton pump inhibitor plus an amount sufficient to protect theproton pump inhibitor from acids and provide undegraded and bioactiveproton pump inhibitor to the blood upon administration (e.g., a final pHof pKa of proton pump inhibitor +0.7 log value will reduce thedegradation to about 10%). Such buffers should interact with hydrogenion at rates that exceed the interaction of hydrogen ion with the protonpump inhibitor. Thus, the solubilities of the buffers and proton pumpinhibiting agents are important considerations because solubility is akey determinant of the rate of interaction of H+ ion with anothercompound.

[0392] Typically, a proton pump inhibitor formulation of the presentinvention comprises two primary components: a proton pump inhibitor andan Essential Buffer. An Essential Buffer may include a buffer orcombination of buffers that interact with HCl (or other acids in theenvironment of interest) faster than the proton pump inhibitor interactswith the same acids. When placed in a liquid phase (usually in water),the Essential Buffer produces and maintains a pH of at least the pKa ofthe proton pump inhibitor. In one embodiment, by raising the pH of theenvironment to the same of the pKa of the proton pump inhibitor plusabout 0.7 log value (or greater), the expected degradation (ionization)can be reduced from about 50% to about 10%. As used herein, the“Essential pH” is the lowest pH of the environment of interest needed tominimize or eliminate the acid-induced degradation of the proton pumpinhibitor. The buffering agent(s) employed may raise the pH of theenvironment to the Essential pH such that 30%, 40% or 50% of the protonpump inhibitor is undegraded, or be present in an amount sufficient tosubstantially protect (i.e., greater than 50% stability) the proton pumpinhibitor.

[0393] In another embodiment, the Essential pH is the pKa of the protonpump inhibitor. In a further embodiment, the Essential pH is the sum ofthe pKa of the proton pump inhibitor plus log 0.7. A log value of about0.7 is added to the pKa, which represents a decrease of about 5.01187%in stability of the proton pump inhibitor from the pKa plus 1 log value,thus resulting in a stability of approximately 90%, a value widelyaccepted as desirable in pharmaceutical products. In some cases it maybe permissible to accept a value of less than log 0.7.

[0394] One aspect of the invention provides that there is alsosufficient buffer available to provide the neutralization capacity(Essential Buffer Capacity (“EBC”)) to maintain the elevated pH of theenvironment (usually gastric) throughout the dwell time that the protonpump inhibitor is passed from the environment and into the blood.

[0395] B. Essential Buffers

[0396] Essential Buffers can be divided into two groups: PrimaryEssential Buffers and Secondary Essential Buffers. Every formulation iscombined with, either directly or indirectly, at least one PrimaryEssential Buffer. The Primary Essential Buffers, when used alone or incombination, provide buffering activity below the value that leads totissue irritation or damage and above a lower limit for the Essential pHof the proton pump inhibitor. Secondary Essential Buffers are notrequired in every formulation but can be combined with Primary EssentialBuffers to produce a higher pH and added neutralization capacity for theformulation.

[0397] Determining the type and dose of buffer to protect acid labilesubstituted benzimidazole proton pump inhibiting agents (and otherdrugs) is useful for efficacious proton pump inhibitor delivery to andaction upon parietal cell proton pumps, particularly when the protonpump inhibitor is administered as an immediate release product designedto disintegrate in the stomach rather than a traditional delayed-releaseproduct designed to disintegrate beyond the stomach in higher pHenvironments such as the duodenum. The present compositions and methodsemploy determinations of the nature of the buffer(s) to be used, as wellas calculations to determine Essential pH, buffering capacity, andvolume measurements for individual proton pump inhibitor doses based ontheir respective solubilities and pKa's. Such inventive methods areapplicable for determining the type and amount of buffer(s) necessary toprotect the proton pump inhibitor in an array of environments (e.g.,mouth, esophagus, stomach, duodenum, jejunum, rectal vault, nasogastrictube, or a powder, tablet, capsule, liquid, etc. in storage beforeadministration). Dosage forms in storage may be exposed to variousenvironments, but a typical set of storage conditions includes storageat room temperature (65-80° F.), and minimal or no exposure to heat,cold, light or humidity as is known in the art.

[0398] The present method includes all substituted benzimidazole protonpump inhibiting agents, their salts, esters, amides, enantiomers,racemates, prodrugs, derivatives and the like, and is not limited tothose proton pump inhibiting agents used to exemplify the followingcalculations.

[0399] The Essential Buffering Capacity (“EBC”) is the capacity of aproton pump inhibitor/buffer formulation to resist degradation from itsenvironment. The buffering capacity of a proton pump inhibitor/bufferformulation is primarily derived from components of the formulation thatpossess the ability to combine with acids (H+ions) from the environment.The EBC contributes to both acid neutralization (antacid effect) and tomaintaining an environmental pH>pKa+0.7 to protect proton pumpinhibiting agents from acid degradation throughout the dwell time. ThePrimary Essential Buffer is designed to maintain the pH of stomachcontents (or other environment) at a somewhat constant level within adesired range for a period of time so that the proton pump inhibitor canbe absorbed from the gastric or other environment. Accordingly, theEssential Buffer is generally more rapid in its complexation with HCl(or other acid) than the proton pump inhibitor administered so that theEssential Buffer is capable of protecting the proton pump inhibitor.

[0400] Any weak base, strong base, or combination thereof may be asuitable Essential Buffer. Essential Buffers include, but are notlimited to, electrolytes containing the cations sodium, potassium,calcium, magnesium or bismuth. In addition, amino acids, proteins orprotein hydrolysates can serve as Essential Buffers owing to theirability to rapidly neutralize acid. When proton pump inhibiting agentsare mixed with the Essential Buffer, the proton pump inhibiting agentsmay be in the free base form, such as omeprazole or lansoprazole; in thesodium salt form, such as esomeprazole sodium, omeprazole sodium,rabeprazole sodium, pantoprazole sodium, etc.; or in a magnesium saltform such as esomeprazole magnesium or omeprazole magnesium or calciumsalt forms; or other salt forms. Essential Buffers provide the EssentialBuffering Capacity either alone or in combination with SecondaryEssential Buffers.

[0401] Tribasic sodium phosphate and sodium carbonate are examples ofSecondary Essential Buffers for adjusting the pH of any PrimaryEssential Buffer. Secondary Essential Buffers may assist the PrimaryEssential Buffer in producing the desirable pH_(E) over the dwell time.Secondary Essential Buffers neutralize HCl (or other acids in theenvironment) similarly to the Primary Essential Buffers; however, theyproduce pH values too high to be used alone, as they would lead togastrointestinal mucosal irritation. They are used to increase the pHand provide additional buffering capacity in combination with a PrimaryEssential Buffer.

[0402] Secondary Essential Buffers do not play an important role inprotecting the proton pump inhibitor from early acid-induceddegradation. Because they do not work as rapidly, they do not play amajor role in proton pump inhibitor protection through the dwell time.Other buffers (“Non-Essential Buffers”) can be added to the Primaryand/or Secondary Essential Buffers to provide a latent antacid effectthat extends beyond the antacid effect of Essential Buffers.

[0403] Many additional buffers can be used, alone or in combination, toachieve an effective buffering capacity for proton pump inhibitingagents or acid labile drugs. A desirable characteristic of buffersincludes rapid neutralization of acid environments to greater thanpKa+0.7 for the drug being considered.

[0404] Non-limiting examples of Primary and Secondary Essential Buffersare set forth in Tables 8 and 9 below. TABLE 8 Examples of PrimaryEssential Buffers Essential Buffer Solubility‡ pH§ MW Sodium bicarbonate9.96 g/100 mL   8-8.4 84 Sodium sesquicarbonate  6.3 g/100 mL 9.9-10 174 Dibasic sodium phosphate   10 g/100 mL 8.6-9.3 142 Sodiumtripolyphosphate   6 gm/l00 mL 9.7-10  368 Tetrasodium pyrophosphate   5g/100 mL  9.8-10.3 266 Sodium citrate   72 g/100 mL 5 294 Calciumcitrate   10 mg/100 mL 6.8 498 Calcium carbonate  1.5 mg/100 mL 6.1-7.1100 Magnesium oxide 0.62 mg/100 mL  9.5-10.5 40 Sodium gluconate   60g/100 mL 6-8 218 Sodium lactate   40 g/100 mL 7 112 Sodium acetate  119g/100 mL 8.9 82 Dipotassium phosphate  150 g/100 mL 9.3 174Tetrapotassium pyrophosphate  185 g/100 mL 10.4 330 Potassiumbicarbonate   36 g/100 mL 8.2 100 Calcium lactate   6 g/100 mL 7 218Calcium glycerophosphate   6 g/100 mL 7 210 Calcium gluconate   3 g/100mL 7.4 430 Magnesium lactate   10 g/100 mL 5.5-7.5 269 Magnesiumgluconate   16 g/100 mL 7.3 414

[0405] TABLE 9 Examples of Secondary Essential Buffers These buffers aretoo caustic to be used alone but are suitable for addition in lowquantities to the Primary Essential Buffers from Table 8. EssentialBuffer Solubility‡ pH§ MW Sodium carbonate 45.5 g/100 mL 10.6-11.4 106Potassium carbonate 11.5 138 Sodium phosphate (tribasic)   8 g/100 mL10.7-12.1 163 Calcium hydroxide  185 mg/100 mL 12 74 Sodium hydroxide11.4-13.2 40

[0406] Amino acids can also be employed as Primary or SecondaryEssential Buffers, the doses of which may be calculated according to thefollowing information. TABLE 10 Solubility Three (g/100 g One LetterLetter H2O at Symbol Symbol Amino Acid MW pH 25° C. A Ala Alanine 89 616.65 C Cys Cysteine 121 5.02 Very D Asp Aspartic Acid 133 2.77 0.778 EGlu Glutamic Acid 147 3.22 0.864 F Phe Phenylalanine 165 5.48 2.965 GGly Glycine 75 5.97 24.99 H His Histidine 155 7.47 4.19 I Ile Isoleucine133 5.94 4.117 K Lys Lysine 146 9.59 Very L Leu Leucine 131 5.98 2.426 MMet Methionine 149 5.74 3.381 N Asn Asparagine 132 5.41 3.53 P ProProline 115 6.30 162.3 Q Gln Glutamine 146 5.65 2.5 R Arg Arginine 17411.15 15 S Ser Serine 105 5.68 5.023 T Thr Threonine 119 5.64 Very V ValValine 117 5.96 8.85 W Trp Tryptophan 204 5.89 1.136 Y Tyr Tyrosine 1815.66 0.0453

[0407] References:

[0408]IUPAC-IUB Commission on Biochemical Nomenclature (CBN), Rules forNaming Synthetic Modifications of Natural Peptides, (1966); ARCS.BIOCHEM. BIOPHYS. 121: 6-8 (1967); BIOCHEM. J. 104: 17-19 (1967),corrected 135: 9 (1973); BIOCHEMISTRY 6: 362-364 (1967); BIOCHIM.BIOPHYS. ACTA 133: 1-5 (1967); BULL. SOC. CHIM. BIOL. 49: 325-330 (1967)(in French); EUR. J. BIOCHEM. 1: 379-381 (1967), corrected 45: 3 (1974);Hoppe-Seyler's, Z., PHYSIOL. CHEM. 348: 262-265 (1967) (in German); J.BIOL. CHEM. 242 555-557 (1967); MOL. BIOL. 2: 466-469 (1968) (inRussian); PURE APPL. CHEM. 31: 647-653 (1972); IUPAC Commission onNomenclature of Organic Chemistry (CNOC), Nomenclature of OrganicChemistry, STEREOCHEM. REC. E: (1974), PURE APPL. CHEM. 45:11-30 (1976).See also Biochemical Nomenclature and Related Documents, PORTLAND PRESS.2: 1-18 (1992).

[0409] C. The Essential pH (pH_(E))

[0410] Substituted benzimidazole proton pump inhibiting agents arelabile under acidic conditions. Orally administered proton pumpinhibiting agents must be protected from the strongly acidic conditionsof the stomach, whether acidic from gastric acids or acids introducedthrough tube feeds or other sources. In general, the higher the pH ofthe gastric environment, the greater the stability of the proton pumpinhibitor, and thus the more time it has to undergo absorption into theblood and reach and act upon the proton pumps of the gastric parietalcells.

[0411] As mentioned, the “Essential pH” is the lowest pH of theenvironment of interest needed to minimize or eliminate the acid-induceddegradation of the proton pump inhibitor during the dwell time in theenvironment. It is generally expressed herein as pH range. Such pH isthe pH of the environment in which the proton pump inhibitor/bufferformulation resides. For example, the environment may be a storagecontainer or the stomach. The environment presents a set of conditionsto the proton pump inhibitor/buffer, such as temperature, pH, and thepresence or absence of water. The dwell time is the time that the protonpump inhibitor dwells in a specific environment, i.e., the GI tractprior to its passage into a different environment, i.e. the blood serum.The shelf-life is another example of a dwell time, in which case, thespecific environment may be a container of dry, powdered formulation. Asused herein, “Resultant pH” is the pH that is the result of adding aproton pump inhibitor/buffer formulation to an environment of interest.“Formulation pH” is the pH of the proton pump inhibitor/bufferformulation when it is in liquid form.

[0412] A proton pump inhibitor dose within its calculated pH_(E) rangeis designed to ensure sufficient proton pump inhibitor protection fromacid degradation such that delivery to and action upon proton pumpsoccur. In one desirable embodiment, the pH_(E) is the sum of the pKa ofa given proton pump inhibitor plus about 0.7. The pKa is defined as thepH at which 50% of a chemical is in the ionized form. When the pH of theenvironment equals the pKa of the proton pump inhibitor, then 50%ionization (degradation) of the proton pump inhibitor occurs. However,by adding the factor of 0.7, this ionization is reduced to 90%.

[0413] The Stability Range Factor (“SRF”) is the range of pH elevationin which the lower limit is the sum of the pKa of a given proton pumpinhibitor+0.7 log, and the upper limit is the pH at which elimination ofacid degradation occurs without producing tissue irritation from extremealkalinity. SRF is calculated based on the desirable shelf-life (or adwell time), the environmental pH and the amount of acid expected to beencountered, along with a knowledge of the time of exposure expectedafter the drug is administered and before the drug reaches the blood(i.e., the dwell time).

[0414] The upper limit of the SRF is a function of the tolerability ofthe gastrointestinal mucosa to alkaline substances, which is determinedby the Formulation pH and the concentration of alkaline materialpresented. For practical purposes, pH=10.9 delineates an upper limit ofthe SRF. It is acknowledged that the amount of buffer is an importantaspect of the tissue destructive potential of an alkaline substance.Therefore, the SRF for any given proton pump inhibitor, begins at thesum of the pKa of the proton pump inhibitor+0.7, and extends upwards toa pH of about 10.9.

[0415] The Essential pH used with the SRF establishes a desirable rangefor the stability to the actions of H+ ion (or other acidic component)on the proton pump inhibitor/buffer formulation. Sufficient bufferingcapacity maintains an Essential pH as described below as “EssentialBuffering Capacity.”

[0416] Examples of pH_(E) calculations with SRF for specific proton pumpinhibiting agents are as follows:

[0417] pH_(E) of proton pump inhibitor=pKa of proton pump inhibitor+0.7.

[0418] SRF=the range: pH_(E) to 10.9.

[0419] SRF for omeprazole=(pKa omeprazole+0.7) to 10.9=(3.9±0.7)=4.6 to10.9.

[0420] SRF for lansoprazole=(pKa lansoprazole+0.7) to 10.9=(4.1±0.7)=4.8to 10.9.

[0421] SRF for rabeprazole=(pKa rabeprazole+0.7) to 10.9=(4.9.+0.7)=5.6to 10.9.

[0422] SRF for pantoprazole=(pKa pantoprazole+0.7) to 10.9=(3±0.7)=3.7to 10.9.

[0423] In most instances, the lower end of each of the above ranges isincreased by one pH unit to minimize, by a factor of 10, any localeffects within the stomach that may produce areas of lower pH that mightcause proton pump inhibitor degradation. A value of +1 log value is alsosupported by the observation that weak bases operate most efficiently atneutralizing acid beginning at +1 log value above the pKa.

[0424] For example, one would expect to encounter about 100-150 ml of0.11 to 0.16N HCl in the adult fasting stomach, which is equivalent toabout 12-24 mEq of HCl. Therefore, an equal amount of base willneutralize this acid. If about 12-24 mEq of sodium bicarbonate isemployed as the buffer, the resulting pH will be left at the pKa of theconjugate acid of sodium bicarbonate (carbonic acid), which is about6.14 or greater. This is greater than the lower limit of the pH_(E) foromeprazole of 4.6. Thus, administering 12-24 mEq of sodium bicarbonatewith omeprazole protects greater than 95% of the drug when encountering12-24 mEq of HCl. Because sodium bicarbonate complexes with HCl at arate that exceeds the rate of interaction of omeprazole, it isconsidered a suitable buffer.

[0425] It should be noted that depending on age and disease, the amountof acid to be encountered can be significantly more or less than the12-24 mEq range, but is generally from about 4 mEq to about 30 mEq.

[0426] Using magnesium oxide or magnesium hydroxide in an amount of 12to 24 mEq also provides sufficient neutralizing capacity leaving the pHat approximately 7 (lowered only slightly by the minimal hydrolysis ofmagnesium). However, magnesium hydroxide is not rapid in onset and careshould be taken to ensure that early degradation of the proton pumpinhibitor does not occur. Early degradation can be avoided by making atablet comprising two layers: an inner layer of proton pump inhibitorand sodium bicarbonate, and an outer layer of magnesium hydroxide driedgel or magnesium oxide with suitable disintegrant such that themagnesium oxide would rapidly disintegrate in the stomach.Alternatively, the inner layer can contain the magnesium buffer and theouter layer has the proton pump inhibitor and sodium bicarbonate.

[0427] Additionally, micronization of the slower acting buffer can beused to enhance its ability to combine with acid. Calcium carbonate (andmany other calcium buffers) is a similar slower acting (compared tosodium bicarbonate) but potent buffer. Therefore, if used, it would bebest suited in an outer layer of a tablet formulation with the innerlayer comprising a rapid acting buffer with proton pump inhibitor (orvice versa). Alternatively, mixtures of the buffers can be employed forthe outer layer. If developing a liquid formulation or a powder forreconstitution, a mixture of a rapid acting buffer and slower actingbuffer can be used (e.g., sodium bicarbonate and magnesium oxide,respectively).

[0428] Modifications to the formulations may entail adjusting the pH ofproducts with basic or acidic chemicals, including but not limited to,chemicals described throughout this application. Modifications of bufferpH based on the pH_(E) may or may not be performed in specificinstances, depending upon species, age, disease and other variationsbetween patients.

[0429] D. pKa and Solubility of Proton Pump Inhibiting Agents

[0430] As mentioned above, the pKa of a given proton pump inhibitorindicates inherent stability with respect to acid degradation; the lowerthe pKa, the more stable the proton pump inhibitor. The solubility ofthe proton pump inhibitor will also dictate the rate at which the protonpump inhibitor complexes with, and is degraded by, acid. These twophysicochemical characteristics (pKa and solubility) of the proton pumpinhibitor interact with the physicochemical characteristics of thebuffer(s) (pH, buffering capacity and rate of buffering action) in thepresence of acid in the environment to determine the degradation of theproton pump inhibitor over time. The less soluble a proton pumpinhibitor is in water, the lower the initial degradation when placed inan acidic environment. The following Table 11 elaborates on the time for50% of drug to be degraded (t ½), pKa and solubility in water of severalproton pump inhibiting agents. TABLE 11 Pantoprazole Rabeprazole PHsodium Omeprazole Lansoprazole sodium 1.2 4.6 min 2.8 min 2.0 min 1.3min 5   2.8 hr 1.0 hr 1.1 hr 5.1 4.7 hr 1.4 hr 1.5 hr 7.2 minutes 6   21 hr 7.3 hr 6.4 hr 7    73 hr  39 hr  35 hr PKa 3 3.9 4.1 4.9Solubility very soluble slightly very slightly Very soluble solublesoluble

[0431] Although pantoprazole sodium, with a pKa of 3, is inherently morestable in an acidic environment than other proton pump inhibitingagents, it is also very soluble in water and thus could undergo 50%degradation in an acidic stomach with a pH of 1.2 in less than 5minutes. Therefore, it is important for the buffer(s) used withpantoprazole sodium to interact with H+ ion (or other acidic substances)more rapidly than the pantoprazole sodium interacts with such acids andmaintain the rapid complexation through the dwell time; otherwise,additional dosing of buffer may be required. The overall pH of thegastric contents should be kept at least at the pKa+0.7 (i.e., 3.7) fromthe time the proton pump inhibitor in solution comes into contact withthe gastric acid continuing throughout the dwell time. Essential Buffersfor liquid formulations of pantoprazole sodium include those bufferswhose conjugate acids possess a pKa>3.7 and which are very soluble(e.g., potassium bicarbonate and sodium bicarbonate) Oral solidformulations likewise would require buffers whose conjugate acidpossesses a pKa>3.7 and rapid complexation potential. Most magnesium,calcium and aluminum salts are not suitable unless the pantoprazolesodium is placed (with or without additional buffer) in an inner portionof a tablet or capsule with such antacids, and surrounded by a rapidacting buffer with a rapid disintegrant. Another formulation method forpantoprazole is to decrease its solubility such as by selecting a lesssoluble salt form or the non-salt form, pantoprazole.

[0432] Rabeprazole sodium is also very soluble in water and couldundergo 50% degradation in an acidic stomach with a pH of 1.2 in lessthan 1.5 minutes. It is not very stable to acid degradation due to itshigher pKa of 4.9. A suitable buffer(s) for rabeprazole sodium interactswith H+ ion (or other acidic substances) more rapidly than therabeprazole sodium interacts with such acids to prevent earlydegradation, and should possess high neutralizing capacity to enablerabeprazole to survive through the dwell time. Sodium or potassiumbicarbonate would be good choices in this instance.

[0433] Another option for rabeprazole sodium (as well as any sodium saltof a proton pump inhibitor, which would tend to be more soluble than thebase form) is to reduce the solubility of rabeprazole sodium when inaqueous form such as using a less soluble salt form or using thenon-salt form. This decreases early degradation because the rabeprazolemust first undergo dissolution in water before it is degraded by acid.In this embodiment, the suitable buffer(s) for rabeprazole sodium shouldpossess high neutralizing capacity to enable rabeprazole to survivethrough the dwell time.

[0434] For proton pump inhibiting agents that possess high pKa's, suchas rabeprazole sodium, a two-part liquid formulation can be utilized.The liquid part has the proton pump inhibitor and a high pH, but a lowmEq buffering capacity. The liquid part is added to a second part thatpossesses a lower pH but a higher mEq buffering capacity. When these twoparts are added together just prior to administration, a formulationwith a lower pH and a higher buffering capacity is produced which willneutralize stomach acid but not be too caustic to tissues. Examples ofsuch formulations are provided below.

[0435] For highly soluble proton pump inhibiting agents, the formulationmay be produced in a solid dosage form such as a tablet, capsule orpowder with a buffer(s), which disintegrate and reach solution at a ratethat exceeds the proton pump inhibitor and thereby provides theEssential pH for protection of the proton pump inhibitor prior to itsdissolution and interaction with the acid in the environment. Further,the tablet or capsule may be formulated to possess an outer portion ofbuffer and an inner portion comprising proton pump inhibitor, or a blendof proton pump inhibitor and buffer. Additional methods includeformulating the buffer in a smaller particle size (e.g., micronized) andthe proton pump inhibitor in a larger particle size. This results in thedisintegration of the buffer component prior to disintegration of theproton pump inhibitor component. All of these methods of formulation aimto create an environment of stability for the proton pump inhibitorduring the dwell time.

[0436] The dosage form may affect the suitability of a buffer for use ina formulation. For example, magnesium oxide is a buffer with highbuffering capacity but slow onset when formulated as a tablet. However,when formulated as a powder, or a tablet of low compression, or withtablet disintegrants such as pregelatinized starch, it disintegratesmore rapidly.

[0437] Omeprazole base is only slightly soluble in water and, as such,less of the drug is subject to early and continued degradation. Thesoluble portion of omeprazole is vulnerable to early degradation in thegastric environment. Dissolution of the remaining insoluble portion isexpected to occur within minutes of encountering the water of thegastric secretions. This dissolution time provides some protectionagainst early degradation provided that relatively low volumes of waterare used during delivery or in the product formulation. After severalminutes in the gastric environment, upon complete dissolution,omeprazole could undergo 50% degradation in less than 3 minutes.Omeprazole is moderately stable owing to its pKa of 3.9. A suitablebuffer(s) for omeprazole is rapid acting and possesses at least moderateneutralizing capacity to enable omeprazole to survive through the dwelltime.

[0438] As used herein, “rapid acting” in the context of a buffer means abuffer that raises the pH of the environment to greater than or equal tothe pH_(E) of a particular proton pump inhibitor in a time sufficient toprevent significant degradation of the proton pump inhibitor. In oneembodiment, the rapid acting buffer raises the pH to at least the pKa ofthe proton pump inhibitor plus 0.7 log value within 10 minutes.

[0439] Preferred buffer(s) produce an environment where the Resultant pHof the environment is equal to or greater than the Essential pH suchthat: (1) the onset of pH change to equal to or greater than thepH_(E)+0.7 begins before the acid-induced degradation of the proton pumpinhibitor occurs, and (2) the Resultant pH at or greater than thepH_(E)+0.7 lasts throughout the dwell time, which is typically a minimumof 30 minutes in the case of gastric emptying for an adult. It isdesirable that the buffer be rapid acting to minimize early acid-induceddegradation. The most rapid acting buffers are water soluble (or solublein the environment). High solubility, however, is not an absolutenecessity as magnesium oxide and calcium carbonate, both only slightlysoluble, are capable of significant complexation with gastric acidalbeit at a slower rate. If a dry formulation is used, such as a tablet,the particle size of the buffer(s) can be reduced to enhance thedissolution rate while the particle size of the proton pump inhibitorcan be increased. Disintegrants can be added to enhance the availabilityof poorly soluble buffers.

[0440] Lansoprazole base is very slightly soluble in water and, as such,less of the drug is subject to early degradation. The soluble portion isvulnerable to early degradation. Dissolution of the remaining insolubleportion is expected to occur within several minutes of encountering thewater of the gastric secretions. This dissolution time provides someprotection against early degradation provided that relatively lowvolumes of water are used for delivery or in the product formulation.After several minutes, upon complete dissolution, lansoprazole couldundergo 50% degradation in 2 minutes. Lansoprazole is moderately stableowing to its pKa of 4.1. A suitable buffer(s) for lansoprazole should berapid acting, and should possess moderate to high neutralizing capacityto enable lansoprazole to survive through the dwell time. The pH of thegastric contents (or other environment) should be kept at greater thanabout 4.8 from the time the proton pump inhibitor in solution comes intocontact with the gastric acid continuing throughout the dwell time.

[0441] E. Calculating the Acid Neutralizing Capacity of Buffers

[0442] The acid neutralizing capacity (“ANC”) of soluble buffers may beused to assist in selecting a preferred amount of buffer(s) needed toprovide the EBC. The ANC uses both the formula weight (FWt.) and thevalence to determine buffering capacity.

[0443] An example of an ANC calculation for sodium bicarbonate is asfollows:

[0444] Sodium Bicarbonate, Na⁺HCO₃ ⁻, FWt.=84, valence=1. The conversionequation from equivalent weight to grams is:

[0445] (Equivalent Weight (“EW”))({fraction (1/1000)} mmol)(1 mmol/1mEq)=grams of NaCHO₃

[0446] EW=(FWt.)/(valence)=84/1=84 g/mol.

[0447] (84 g/mol)(1 mol/1000 mmol)(1 mmol/1 mEq)(4 mEq)=0.34 g NaHCO₃needed for 4 mEq of buffering capacity.

[0448] Accordingly, for 10 mEq, one needs 0.840 g NaHCO₃, and for 30mEq, 2.52 gm is required. The range of 4-30 mEq is used because that isthe range of mEq of acid to be encountered in most patients.

[0449] The ANCs of other buffers are similarly calculated. ANCdeterminations are from Drake and Hollander, Neutralizing Capacity AndCost Effectiveness Of Antacids, ANN INTERN. MED. 109:215-17 (1981).Generally, the formulations of the present invention need about 4 toabout 30 mEq of buffering capacity although higher amounts could be usedin some patients.

[0450] Sodium bicarbonate in solution possesses a pH>pH_(E) ofomeprazole and rapidly neutralizes acidic environments. As stated above,rapid complexation with HCl is a desirable characteristic of anEssential Buffer. Ideally, but not necessarily required as indicated informulations that contain a tablet in a tablet, the Essential Buffercomplexes with the acid at a faster rate than the proton pump inhibitorit is intended to protect.

[0451] In selecting Essential Buffers, a knowledge of buffering capacityis also useful since they possess differing pHs at variousconcentrations. The magnitude of the resistance of a buffer to pHchanges is referred to as buffer capacity (Beta). It has been defined byKoppel, Spiro and Van Slyke as the ratio of the increment of strong acid(or base) to the change in pH brought about by addition of acid. Thefollowing formula is used to measure buffer capacity: Buffercapacity=the increment (in gram equivalents per liter) of strong acidadded to the buffer solution to produce a pH change (change as measuredin absolute terms), or buffer capacity=change in acid/change in pH.Improvements in the formula have been made to improve the precision, andthese form the basis for mathematical comparison of buffers forconsideration. See Koppel, BioChem, Z. (65) 409-439 (1914), Van Slyke,J. BIOL. CHEM. 52:525 (1922).

[0452] When the proton pump inhibitor/buffer formulation is placed inthe environment, the proton pump inhibitor is subject to degradation bythe acid in that environment. As depicted in FIG. 9, proton pumpinhibitor solubility, the pKa of the proton pump inhibitor, and theamount and concentration of acid (H+ ion) encountered in the environmentare variables that can be used to determine the appropriate candidate asan Essential Buffer. Early degradation occurs when the soluble portionof the proton pump inhibitor (that portion available for immediateinteraction with H+ ion) undergoes hydrolysis by H+ ion. proton pumpinhibiting agents differ in their solubility and, therefore, those thatare more soluble have a potential for a higher portion of proton pumpinhibitor degraded by early interaction with H+ ion. The pKa of theproton pump inhibitor and the pH of the environment of the stomach (orother site of interest) after addition of the proton pumpinhibitor/buffer formulation (Resultant pH) can be used to determine thedesirable Essential Buffer. By measuring the Resultant pH over time, thepH data versus time can be plotted as seen in FIG. 9. The graph of pHover time can then be used to evaluate various buffers.

[0453] Such a graph can be developed for a potential buffer or buffercombination using the Rossett-Rice test (Rosset N E, Marion L: An InVitro Evaluation Of The Efficacy Of The More Frequently Used AntacidsWith Particular Attention To Tablets. ANTACIDS 26: 490-95 (1954),modified with continual addition of simulated gastric fluid. See USPXXIII, The United States Pharmacopeia, 23^(rd) Revision, United StatesPharmacopeia Convention, Inc. Briefly, the test employs 150 mL ofsimulated gastric fluid consisting of 2 Gm of sodium chloride and 3.2 Gmof pepsin, which are dissolved in 7 mL of 1N HCl, q.s. to 1000 mL withdistilled water. The pH of the simulated gastric fluid is 1.2. Acontainer of 150 mL of this fluid is stirred at 300 rpm±30 rpm with amagnetic stirrer and kept at 37.1° C. A pH electrode is kept in theupper region of the solution. The test buffer or the subject formulationis added to the container to start the evaluation. At 10 minutes, acontinuous drip of simulated gastric fluid is added to the testcontainer at a rate of 1.6 ml/min to simulate gastric secretion.Approximately 1.6 mL/min is removed from the test container to keep thevolume in the test container constant. The evaluation continues for atleast 90 minutes.

[0454] This methodology allows for a dynamic evaluation of bufferingcapacity in a model designed to mimic a fasting human stomach. It hasbeen described in part for use in evaluating antacids by Beneyto J E,et. al., Evaluation of a New Antacid, Almagate, ARZNEIM-FORSCH/DRUG RES1984; 34 (10A): 1350-4; Kerkhof N J, et al, pH-Stat Tiration of AluminumHydroxide Gel, J. PHARM. SCI. 1977; 66:1528-32.

[0455] Using this method, a pH tracing can be developed for evaluatingbuffers as well as finished products. In addition, a sample of the testsolution can be taken during the experiment to evaluate the extent ofproton pump inhibitor degradation at various times. Those buffers with asuitable profile as exemplified in FIG. 9 able to maintain pH greaterthan or equal to pH_(E) for 30 minutes or greater, can be consideredsuitable Essential Buffers. In one embodiment, as depicted in FIG. 9,the pH was recorded over 10 second intervals.

[0456] A number of buffers may be applicable for use as EssentialBuffers. Therefore, once an Essential Buffer is chosen, the amountnecessary to provide the EBC is calculated. As used herein, the. EBC isthe buffering capacity, or amount of alkaline buffer, included in thedose and calculated to maintain the Essential pH range and therebyprotect any substituted benzimidazole proton pump inhibitor in thegastric (or other) environment. In patients requiring continuing protonpump inhibitor administration (e.g. daily), more buffering capacity maybe necessary with the first dose or first few doses than with subsequentdoses because the proton pump inhibitor may encounter more acid with theinitial doses. Subsequent doses will require less buffering capacitybecause the initial proton pump inhibitor doses will have reducedgastric acid production. The EBC could therefore be reduced insubsequent doses. The product's buffering capacity may be formulated asdesired, for instance with respect to patient age, gender or species.

[0457] Experimental data from adult human subjects showed an effectiveEBC range of a first dose of omeprazole to be about 4 to about 20 mEq(“EBC-O range”) of sodium bicarbonate, with a range of about 12 to about25 mEq suitable in most instances. Subsequent doses of omeprazolerequire less EBC, with a range of about 4 to 15 mEq sodium bicarbonate.In one embodiment, this latter EBC range proved optimal for anomeprazole suspension administered to patients with varying degrees ofgastrointestinal transit and acid output, based on a knowledge of basaland maximal acid outputs of 2 and 25 mEq/hour, respectively. Thesestudies have been reported in Phillips J. O. et al., CRIT. CARE MED.1996; Lasky et al., J. TRAUMA 1998.

[0458] Based on the EBC-O range, the above ANC calculation can beemployed. Additionally, it is expected to encounter about 100-150 mL of0.1 N HCl (equating to about 12-24 mEq of acid) in a fasting stomach.Variations in the acid encountered in the environment will affect theEssential Buffering Capacity required. The above EBC ranges relate toadult patients. Children, however, produce less acid per unit time incomparison to adults. Therefore, depending on the patient population,the amount of Essential Buffering Capacity required may be altered.

[0459] Numerous references are available to assist the skilled artisanin identifying a suitable buffer companion with a proton pump inhibitorto determine the desirable characteristics stated herein. See, e.g.,Holbert, et. al., A Study of Antacid Buffers: I. The Time Factor inNeutralization of Gastric Acidity, J. AMER. PHARM. ASSN. 36: 149-51(1947); Lin, et. al., Evaluation of Buffering Capacity and AcidNeutralizing pH Time Profile of Antacids, J. FORMOSA MED. ASSN. 97 (10)704-710 (1998); Physical Pharmacy, pp 169-189; Remington: The Scienceand Practice of Pharmacy (2000).

[0460] F. The Desirable Volume

[0461] The Desirable Volume (“DV”) of a proton pump inhibitor dose mayaffect proton pump inhibitor delivery to and action upon parietal cellproton pumps. The DV of a dose is partly based on the EBC. For liquidformulations, a desirable volume should deliver sufficient buffer to actas an antacid to neutralize a substantial amount of gastric or otheracids. For solid formulations such as tablets, a nominal amount of wateror other fluid will be consumed to aid in swallowing the tablet. Liquidpreparations of the present invention use volumes as small as about 2 mlor in excess of about 60 ml. Volumes smaller than 2 ml and larger than60 ml are contemplated, and may be used as desired to suit individualpatients, such as those of advanced or very young age or of differentspecies. Very large volumes may lead to higher amounts of less solubleproton pump inhibiting agents (e.g., omeprazole, lansoprazole baseforms) going into solution, which could result in vulnerability to earlydegradation.

[0462] For instance, volumes smaller than about 2 ml may be used innewborns or premature infants, or in small animals, because of theirsmaller stomach size. Also, a large DV may be required for dosesformulated with dilute buffer concentrations, to achieve the EBC. Therelationship between the EBC and DV is in part shown below:

f EBC(mg buffer)=Buffer conc.(mg/ml)×DV(ml),

[0463] then DV(ml)=EBC(mg)/Buffer conc.(mg/ml).

[0464] Alternatively, mEq can be substituted for mg in the formula.

[0465] G. Secondary Components of the Formulations

[0466] Secondary components are not required but may be used to enhancethe pharmacological action or as pharmaceutical aids. Secondarycomponents may include, but are not limited to, parietal cell activatorsand other ingredients. Parietal cell activators, as discussed above, arecompounds that produce an increase in proton pump activity such thatproton pumps are relocated from storage sites of the parietal cell, i.e.tubulovesicles, to the site of H+, K+ exchange at the secretorycanaliculus. A parietal cell activator may also serve other functions.For example, sodium bicarbonate is an Essential Buffer as well as aparietal cell activator, chocolate is a parietal cell activator and aflavoring agent, and aspartame, which contains phenylalanine, is asweetener as well as a parietal cell activator.

[0467] Parietal cell activators can be divided into four groups: 1)rapid acting buffers that are weak bases, strong bases or combinationsthereof that also produce a rapid onset of effect (the pH drops rathersuddenly after the buffer is exhausted; these buffers typically causethe pH of the stomach to rise to above 5); 2) amino acids, proteinhydrolysates and proteins; 3) calcium containing compounds such ascalcium chloride or calcium carbonate; and 4) compositions such ascoffee, cocoa, caffeine and peppermint.

[0468] The other ingredients comprise components of a formulation thatare secondary to the primary components. Other ingredients include, butare not limited to, thickening agents, flavoring agents, sweeteners,antifoaming agents (such as simethicone), preservatives, antibacterialor antimicrobials agents (such as cefazolin, amoxicillin,sulfamethoxazole, sulfisoxazole, erythromycin and other macrolides suchas clarithromycin or azithromycin), and Secondary Essential Buffers.

[0469] Desirable flavoring agents may be added to the dosage forms, andmay or may not need to be buffered to the pH_(E). Flavoring agents withpH values inherently suitable to the range of pH_(E) values of protonpump inhibiting agents include, but are not limited to, apple, caramel,meat, chocolate, root beer, maple, cherry, coffee, mint, licorice, nut,butter, butterscotch, and peanut butter flavorings, used alone or in anycombination. Similarly, all substances included in the formulation ofany proton pump inhibitor product, including but not limited to,activators, antifoaming agents, potentiators, antioxidants,antimicrobial agents, chelators, sweeteners, thickeners, preservatives,or other additives or substances may be buffered to the pH_(E).

[0470] H. Examples Utilizing the Calculations

[0471] The pH_(E), the EBC, and the DV of a proton pump inhibitor dosemay affect proton pump inhibitor delivery to, and action upon, parietalcell proton pumps. The following calculations tailor an Essential Bufferdose for any substituted benzimidazole proton pump inhibitor to promoteproton pump inhibitor efficacy in an oral administration.

[0472] Example 1: To deliver a 20 mg dose of omeprazole (pKa=3.9) insodium bicarbonate:

[0473] Step 1: The pH_(E) of omeprazole=pKa of omeprazole+0.7=4.6. TheSRF of omeprazole=pH_(E) to 10.9=4.6 to 10.9. At a Formulation pH of 4.6to 10.9, the conjugate base of sodium bicarbonate (carbonic acid) has apKa of 6.14. Therefore, an amount of sodium bicarbonate equivalent tothe amount of acid to be encountered would produce a pH of 6.14, whichis within the SRF of 4.6 to 10.9. Sodium bicarbonate would make asuitable choice as a buffer.

[0474] Step 2: The EBC=4 to 30 mEq buffering capacity equivalent.

[0475] Step 3: To determine the amount of sodium bicarbonate toadminister with the omeprazole, the ANC for sodium bicarbonate iscalculated. The ANC for sodium bicarbonate (MW=84 for 4-30mEq)=(EW)({fraction (1/1000)} mmol)(1 mmol/1 mEq)(EBC)

[0476] EW=MW/(valence)=84/1=84 g/mol

[0477] (84 g/mol)(1 mol/1000 mmol)(1 mmol/1 mEq)(4 to 30 mEq)=0.34 g to2.52 g

[0478] Step 4: For liquid formulations, if the DV=20 ml, thenDV=Essential Buffer (EB) (mg)/Buffer conc. (mg/ml)

[0479] Buffer conc.=EB/DV=340 mg to 2520 mg/20 ml=17 mg/ml to 126 mg/ml.

[0480] Therefore, for 20 mg of omeprazole to be adequately buffered in20 ml of solution, the concentration of sodium bicarbonate should be 17to 126 mg/ml.

[0481] Example 2: To deliver a 20 mg dose of omeprazole (pKa=3.9) indibasic sodium phosphate:

[0482] Step 1: The pH_(E) of omeprazole=pKa of omeprazole+0.7. The SRFof omeprazole=(3.9+0.7) to 10.9=4.6 to 10.9.

[0483] Step 2: The EBC=4 to 30 mEq buffering capacity equivalent.

[0484] Step 3: To determine the amount of dibasic sodium phosphate toadminister with the omeprazole, the ANC for dibasic sodium phosphate iscalculated. The ANC for dibasic sodium phosphate (MW=142)=(EW)({fraction(1/1000)} mmol)(1 mmol/1 mEq)(EBC).

[0485] EW=MW/(valence)=142/2=71 g/mol.

[0486] (71 g/mol)(1 mol/{fraction (1/1000)} mmol)(1 mmol/1 mEq)(4 to 30mEq)=0.28 g to 2.13 g

[0487] Step 4: For liquid formulations, if the DV=20 ml, then DV=EB(mg)/Buffer conc. (mg/ml)

[0488] Buffer conc.=EB/DV=280 mg to 2130 mg/20 ml=14 mg/ml to 107 mg/ml.

[0489] Therefore, for 20 mg of omeprazole to be adequately buffered in20 ml of solution, the concentration of dibasic sodium phosphate shouldbe 14 to 107 mg/ml. The pka of disodium phosphate is 7.21. Therefore, anamount of disodium phosphate equivalent to the amount of acid to beencountered would produce a pH of approximately 7.2. Thus, disodiumphosphate would make a suitable choice as a buffer.

[0490] Example 3: To deliver a 30 mg dose of lansoprazole (pKa=4.1) insodium bicarbonate:

[0491] Step 1: The pH_(E) of lansoprazole=pKa of lansoprazole+0.7. TheSRF of lansoprazole=(4.1±0.7) to 10.9=4.8 to 10.9.

[0492] Step 2: The EBC=4-30 mEq buffering capacity equivalent.

[0493] Step 3: To determine the amount of sodium bicarbonate toadminister with the lansoprazole, the ANC for sodium bicarbonate iscalculated. The ANC for sodium bicarbonate (MW=84)=(EW)({fraction(1/1000)} mmol)(1 mmol/1 mEq)(EBC)

[0494] EW=MW/valence=84/1 g/mol

[0495] (84g/mol)(1 mol/1000 mmol)(1 mmol/1 mEq)(4 to 30 mEq)=0.34 g to2.52 g

[0496] Step 4: For liquid formulations, if the DV=20 ml, then DV=EB(mg)/Buffer conc. (mg/ml)

[0497] Buffer conc.=EB/DV=340 mg to 2520 mg/20 ml=17 mg/ml to 126 mg/ml.

[0498] Therefore, for 30 mg of lansoprazole to be adequately buffered in20 ml of solution, the concentration of sodium bicarbonate should beabout 17 to about 126 mg/ml.

[0499] Example 4: To deliver a 40 mg dose of pantoprazole (pKa=3) insodium bicarbonate:

[0500] Step 1: The pH_(E) of pantoprazole=pKa of pantoprazole+0.7. TheSRF of pantoprazole=(3+0.7) to 10.9=3.7 to 10.9.

[0501] Step 2: The EBC=4-30 mEq buffering capacity equivalent.

[0502] Step 3: To determine the amount of sodium bicarbonate toadminister with the pantoprazole, the ANC for sodium bicarbonate iscalculated. The ANC for sodium bicarbonate (MW=84)=(EW)({fraction(1/1000)} mmol)(1 mmol/1 mEq)(EBC)

[0503] EW=MW/(valence)=84/1 g/mol

[0504] (84 g/mol)(1 mol/1000 mmol)(1 mmol/1 mEq)(4 to 30 mEq)=0.34 g to2.52 g

[0505] Step 4: For liquid formulations, if the DV=20 ml, then DV=EB(mg)/Buffer conc. (mg/ml)

[0506] Buffer conc.=EB/DV=340 mg to 2520 mg/20 ml=17 mg/ml to 126 mg/ml.

[0507] Therefore, for 40 mg of pantoprazole to be adequately buffered in20 ml, the concentration of sodium bicarbonate should be about 17 to 126mg/ml.

[0508] Example 5: To deliver a 20 mg dose of rabeprazole (pKa=5) insodium phosphate dibasic:

[0509] Step 1: The pH_(E) of rabeprazole pKa of rabeprazole+0.7. The SRFof rabeprazole=4.9±0.7) to 10.9=5.6 to 10.9.

[0510] Step 2: The EBC=4-30 mEq buffering capacity equivalent.

[0511] Step 3: Therefore, to determine the amount of sodium phosphatedibasic to administer with the rabeprazole, the ANC for potassium sodiumdibasic is calculated. The ANC for sodium phosphate dibasic (duohydrate)(MW=174)=(EW)({fraction (1/1000)} mmol)(1 mmol/1 mEq)(EBC)

[0512] EW=MW/valence=178/1 g/mol

[0513] (178g/mol)(1 mol/1000 mmol)(1 mmol/1 mEq)(4 to 20 mEq)=0.712 g to5.34 g sodium phosphate dibasic.

[0514] Step 4: For liquid formulations, if the DV=20 ml, then DV=EB(mg)/Buffer conc. (mg/ml).

[0515] Buffer conc.=EB/DV=0.712 g to 2 g/20 ml=35.6 mg/ml to 100 mg/ml.In this case, the solubility of disodium phosphate would limit theamount that could be dissolved in 20 mL. Obviously, this would exceedthe solubility of disodium phosphate (sodium phosphate dibasic).Therefore, for 20 mg of rabeprazole to be adequately buffered in 20 mlof solution, the concentration of sodium phosphate dibasic should beabout 35.6 mg/ml to 100 mg/ml at a pH range of about 6.9 to 10.9. Thepka of disodium phosphate is 7.21. Thus, an amount of disodium phosphateequivalent to the amount of acid to be encountered would produce a pH ofapproximately 7.2. Accordingly, disodium phosphate would make a suitablechoice as a buffer.

[0516] It should be noted that the suitability of buffers relates totheir use immediately after mixing. In order to enhance the shelf-life,higher pH values would be anticipated within the range of acceptablepH_(E) for a given proton pump inhibitor. As an example, rabeprazolesuspensions containing various buffers were evaluated for color changebecause degradation of proton pump inhibiting agents results in a colorchange to brown or black. All buffer suspensions started out white incolor. After 2 weeks the following observations were made: 20 mgRabeprazole in Various Buffers Stored Under Refrigerated Conditions AsSuspensions Original Color 14 pH Buffer Color days at 14 days Sodiumbicarbonate 800 mg/10 mL white brown 8.3 Disodium phosphate 800 mg/10 mLwhite white 10.3 Disodium phosphate 700 mg; white white 10.5 Trisodiumphosphate 100 mg/10 mL

[0517] Similar calculations may be performed for any substitutedbenzimidazole proton pump inhibitor and appropriate buffer(s) including,but not limited to, those exemplified above. One skilled in the art willappreciate that the order of the above steps is not critical to theinvention. The above calculations may be used for formulationscomprising one or more proton pump inhibitor and one or more buffers.

[0518] I. Veterinary Formulations

[0519] Horses produce stomach acid continuously throughout the day. Itis the basal acid secretion from the stomach in the absence of feedingthat is responsible for the erosion of the squamous mucosa in thestomach and ulcers. Horses on pasture normally secrete a continuoussupply of saliva, which buffers the stomach acid. When horses are beingridden regularly, trained for shows or prepared for sales, they areusually kept in stalls much of the day. Under these conditions, thenatural salivary buffering mechanism is disrupted and acid indigestionoften results.

[0520] Almost 40 to about 100 mEq of buffer capacity should provideapproximately 2.5 hours of neutralization for a horse. The usual dose ofomeprazole ranges from 0.7 to 1.5 mg/kg/day (doses up to 4 mg/kg/day maybe required) and a typical weight for a horse is 500 kg. Similar dosagesare expected for rabeprazole and lansoprazole.

[0521] Dogs can also suffer from ulcers and their dosage isapproximately 1 mg/kg/day. The following formulations are designed foruse in horses but smaller amounts can be used in dogs with an EBC of 10to 20 mEq. Formulation 5: Veterinary Formulation of Omeprazole Thisformulation is particularly well suited for animals rather than humansbecause the dose of proton pump inhibitor is high. EBC = 75 mEqEssential pH (omeprazole pKa = 3.9 + 0.7 ≧ 4.6) Proton pump inhibitor:Omeprazole powder 500 mg (a range of 350 to 700 mg) Primary EssentialBuffer(s): Sodium bicarbonate  5 g (59.5 mEq) Dibasic sodium phosphate(anhydrous) 2 g (14 mEq) Optional Secondary Essential Buffer(s):Tribasic sodium phosphate 200 mg. (1.2 mEq)

[0522] Powders of the above compounds are combined as is known in theart to create a homogenous mixture with the addition of a thickener suchas guar gum 350 mg, artificial maple flavor powder 100 mg, thaumatinpowder 10 mg (to mask the bitterness of omeprazole), and sucrose 25 Gm.Q.s. to 100 mL with distilled water to achieve a final omeprazoleconcentration of 5 mg/mL. Different volumes of water may be added toachieve omeprazole concentrations ranging from about 0.8 to about 20mg/mL.

[0523] Alternatively, this formulation may be divided into two parts.The dry part may be reconstituted with the liquid part at the time ofuse. Formulation 6: Veterinary Formulation of Lansoprazole Essential pH(lansoprazole pKa = 4.1 + 0.7 ≧ 4.8) EBC = 71.4 mEq Proton pumpinhibitor: Lansoprazole powder 750 mg Primary Essential Buffer(s):Sodium bicarbonate  6 g (71.4 mEq)

[0524] Powders of the above compounds are combined as is known in theart to create a homogenous mixture with the addition of a thickener suchas xanthan gum 300 mg, artificial peanut butter flavor powder 100 mg,and sucrose 35 Gm. Q.s. to 100 mL with distilled water to achieve afinal lansoprazole concentration of 7.5 mg/mL. The suspension should berefrigerated after reconstitution. Different volumes of water may beadded to achieve lansoprazole concentrations ranging from 0.8 to 20mg/mL.

[0525] Alternatively, this formulation may divided into two parts. Thedry part may be reconstituted with the liquid part at the time of use.Formulation 7: Veterinary Formulation of Lansoprazole Essential pH(lansoprazole pKa = 4.1 + 0.7 ≧ 4.8) EBC = 63.3 mEq Proton pumpinhibitor: Lansoprazole powder 750 mg Primary Essential Buffer(s) Sodiumbicarbonate  5 g (59.5 mEq) Secondary Essential Buffer(s): Sodiumcarbonate 400 mg* (3.8 mEq)

[0526] Powders of the above compounds are combined as is known in theart to create a homogenous mixture with the addition of a thickener suchas hydroxypropyl methyl cellulose 300 mg, artificial maple flavor 100mg, and sucrose 35 Gm. Q.s. to 100 mL with distilled water to achieve afinal lansoprazole concentration of 7.5 mg/mL. Different volumes ofwater may be added to achieve lansoprazole concentrations ranging from0.3 to 20 mg/mL.

[0527] Alternatively, this formulation may divided into two parts. Thedry part may be reconstituted with the liquid part at the time of use.Formulation 8: Veterinary Formulation of Esomeprazole MagnesiumEssential pH (esomeprazole pKa = 3.9 + 0.7 ≧ 4.6) EBC = 53.2 mEq Protonpump inhibitor: Esomeprazole magnesium powder 500 mg Primary EssentialBuffer(s): Sodium bicarbonate  5 g (47.6 mEq) Dibasic sodium phosphate800 mg (5.6 mEq)

[0528] Powders of the above compounds are combined as is known in theart to create a homogenous mixture with the addition of a thickener suchas hydroxypropyl cellulose 300 mg, artificial butterscotch flavor 100mg, thaumatin powder 5 mg, and sucrose 30 Gm. Q.s. to 100 mL withdistilled water to achieve a final esomeprazole concentration of 7.5mg/mL. Different volumes of water may be added to achieve esomeprazoleconcentrations ranging from 0.8 to 20 mg/mL. Formulation 9: VeterinaryFormulation of Pantoprazole Sodium or Pantoprazole Base Powder EssentialpH (pantoprazole sodium pKa = 3 + 0.7 ≧ 3.7) EBC = 53.8 mEq Pantoprazolesodium or pantoprazole 1000 mg powder Primary Essential Buffer(s):Sodium bicarbonate 4 g (47.6 mEq) Secondary Essential Buffer(s):Trisodium phosphate 1000 mg* (6.2 mEq)

[0529] Powders of the above compounds are combined as is known in theart to create a homogenous mixture with the addition of a thickener suchas hydroxypropyl cellulose 300 mg, artificial butterscotch flavor 100mg, thaumatin powder 5 mg, and sucrose 30 Gm. Q.s. to 100 mL withdistilled water to achieve a final pantoprazole concentration of 10mg/mL. Different volumes of water may be added to achieve esomeprazoleconcentrations ranging from 0.2 to 20 mg/mL. Formulation 10: VeterinaryFormulation: Buffer Base Without Proton Pump Inhibitor EBC = 71.4 mEqPrimary Essential Buffer: Sodium bicarbonate 6 g 71.4 mEq OptionalSecondary Essential Buffer: Tribasic sodium phosphate 1000 mg*

[0530] Powders of the above compounds are combined as is known in theart to create a homogenous mixture with the addition of a thickener suchas hydroxypropyl cellulose 300 mg, artificial butterscotch flavor 100mg, thaumatin powder 5 mg, and sucrose 30 Gm. Q.s. to 100 mL withdistilled water. A proton pump inhibitor or other acid-labile drug maybe added by the compounding pharmacist selected from available protonpump inhibiting agents or acid-labile drugs from powder orenteric-coated oral solid dosage forms. Different volumes of water maybe added to achieve proton pump inhibitor concentrations ranging from0.8 to 20 mg/mL. If other acid labile drugs are employed, the range ofconcentrations would be as required to deliver the normal dosage in anacceptable volume of 1 mL to 30 mL. The amount of buffer required toprotect the drug in question will also determine the minimal feasiblevolume. This formulation may be in the form of a one-part product(liquid or dry) or a two-part product (liquid and dry), for examples. Inthe two-part example, the drug to be added to the formulation may beadded to the dry formulation and the liquid part may be added at thetime of use, or the drug may be added to the liquid portion which wouldbe buffered to a pH above that required for disintegration ofenteric-coated drug formulations (typically pH of 6.8 or greater).

[0531] For all of the veterinary and human oral dosage forms disclosedherein, sweeteners, parietal cell activators, thickeners, preservatives,and flavoring agents may also be added. Sweeteners include but are notlimited to corn syrup, simple syrup, sugar, thaumatin, and aspartame.Thickeners include but are not limited to methylcellulose, xanthan gum,carrageenan, and guar gum. Preservatives may be added to retard spoilageand include but are not limited to sodium benzoate, methylparaben andpropylparaben. Flavoring agents in these formulations include but arenot limited to apple, caramel, maple, peanut butter, meat, etc.

[0532] J. Other Formulations

[0533] For all formulations herein, the total amount of Essential Buffermay range from about 4 mEq to about 30 mEq per dose. Formulation 11:Oral Buffer Complex Without Proton Pump Inhibitor (for general use toprotect acid labile drugs) Multidose Composition Primary EssentialBuffer: Dibasic sodium phosphate or sodium 10 g (range 2 g to 10 g)bicarbonate Optional Secondary Essential Buffer: Tribasic sodiumphosphate or 200 mg sodium carbonate Other ingredients: Sucrose 26 gMaltodextrin 2 g Cocoa processed with alkali 1800 mg Corn syrup solids6000 mg Sodium caseinate 100 mg Soy lecithin 80 mg

[0534] Thoroughly blend the powder, then store in a container protectedfrom light and moisture, such as in a foil packet. Preservatives may beadded to retard spoilage and include but are not limited to sodiumbenzoate, methylparaben, and propylparaben. Thickeners such as xanthangum, guar gum, or hydroxymethyl propyl cellulose can be flavoring agentsin these formulations include chocolate, caramel, maple, butter pecanand other flavorings as have been outlined previously. Different volumesof water may be added to achieve proton pump inhibitor concentrationsranging from 0.8 to 20 mg/mL.

[0535] Weigh out approximately 60 g of the formulation. Add proton pumpinhibitor (or other acid-labile drug) typically in the amount equivalentto 10 doses (range 1 dose to 30 doses).

[0536] Q.s. to 100 mL with distilled water. Formulation 12: Oral BufferComplex Without Proton Pump Inhibitor For General Use to Protect AcidLabile Drugs; Protein Free, Multi-Dose Example Primary Essential Buffer:Sodium bicarbonate 5 g (range 2 g to 10 g) (59.5 mEq) Optional:Secondary Essential Buffer None* Other ingredients Sucrose 26 gMaltodextrin 2 g Cocoa processed with alkali 1800 mg Corn syrup solids6000 mg Soy lecithin 80 mg

[0537] Thoroughly blend the powder, then store in a container protectedfrom light and moisture, such as in a foil packet. Weigh outapproximately 60 g of the formulation. Add proton pump inhibitor (orother acid-labile drug) typically in the amount equivalent to 10 doses(range=1 dose to 30 doses).

[0538] Q.s. to 100 mL with distilled water. Different volumes of watermay be added to achieve proton pump inhibitor concentrations rangingfrom 0.8 to 20 mg/mL. Formulation 13: Buffer Complex Without Proton PumpInhibitor For General Use to Protect Acid Labile Drugs; Protein Free,Lactose Free Multidose Example Proton pump inhibitor: None (to be addedlater, e.g. by compounding pharmacist) Primary Essential Buffer(s):Sodium bicarbonate 8 g (range 2 g to 10 g) Other ingredients: Sucrose 26g Maltodextrin 2 g Corn syrup solids 6000 mg Partially hydrogenatedsoybean oil 400 mg Dipotassium phosphate 300 mg Caramel flavor 270 mgSoy lecithin 80 mg Sodium silico aluminate 20 mg Titanium dioxide 10 mg

[0539] Thoroughly blend the powder, then store in a container protectedfrom light and moisture, such as in a foil packet.

[0540] Optional Secondary Essential Buffer:

[0541] Tribasic sodium phosphate 1000 mg

[0542] Weigh out approximately 60 g of the formulation. Add proton pumpinhibitor (or other acid-labile drug) typically in the amount equivalentto 10 doses (range=1 dose to 30 doses). Q.s. to 100 mL with distilledwater. Different volumes of water maybe added to achieve proton pumpinhibitor concentrations ranging from 0.3 to 20 mg/mL. Formulation 14:Buffer Complex Without Proton Pump Inhibitor For General Use to ProtectAcid Labile Drugs; Protein Free, Multi-Dose Example Proton pumpinhibitor: None (to be added later, e.g. by compounding pharmacist)Primary Essential Buffer(s): Dibasic sodium phosphate 8 g (range 2 g to10 g) Other ingredients: Sucrose 26 g Maltodextrin 2 g Butterscotchflavor 270 mg Corn syrup solids 6000 mg

[0543] Thoroughly blend the powder, then store in a container protectedfrom light and moisture, such as in a foil packet.

[0544] Weigh out approximately 60 g of the formulation. Add proton pumpinhibitor (or other acid-labile drug) typically in the amount equivalentto 10 doses (range=1 dose to 30 doses). Q.s. to 100 mL with distilledwater. Different volumes of water may be added to achieve proton pumpinhibitor concentrations ranging from 0.8 to 20 mg/mL. Formulation 15:Buffer Complex Without Proton Pump Inhibitor For General Use to ProtectAcid Labile Drugs; Protein Free, Multi-Dose Example Proton pumpinhibitor: None (to be added later, e.g. by compounding pharmacist)Primary Essential Buffer(s): Sodium bicarbonate 8 g (range 1 g to 10 g)Secondary Essential Buffer(s): Trisodium phosphate 1.5 g (range 0 g to 5g) Other ingredients: Sucrose 26 g Maltodextrin 2 g Butterscotch flavor270 mg Corn syrup solids 6000 mg

[0545] Thoroughly blend the powder, then store in a container protectedfrom light and moisture, such as in a foil packet. Weigh outapproximately 60 g of the formulation. Add proton pump inhibitor (orother acid-labile drug) typically in the amount equivalent to 10 doses(range=1 dose to 30 doses). Q.s. to 100 mL with distilled water.Different volumes of water may be added to achieve proton pump inhibitorconcentrations ranging from 0.8 to 20 mg/mL. Formulation 16: One PhaseLansoprazole 30 mg Tablet Lansoprazole has a pKa of 4.1; thus, theEssential pH = 4.1 + 0.7 ≧ 4.8 Examples of buffers that produce asolution with pH 4.8 or greater and produce the Essential BufferingCapacity include, but are not limited to, sodium bicarbonate, sodiumcarbonate, dibasic sodium phosphate, and dipotassium phosphate. Enoughpowder for 11 tablets is weighed out: Proton pump inhibitor:Lansoprazole powder  330 mg Primary Essential Buffer(s): Sodiumbicarbonate USP 5500 mg Dibasic sodium phosphate 2200 mg

[0546] The resultant powder is thoroughly mixed. Then 720 mg of thehomogeneous mixture is poured into a tablet reservoir (½ inch diameter)and pressed through a full motion of the press as is known in the art.The resultant tablet contains: Lansoprazole  30 mg Sodium bicarbonateUSP 500 mg Disodium hydrogen phosphate 200 mg

[0547] The tablet contains 6 mEq sodium bicarbonate and 1.4 mEq dibasicsodium phosphate. Variations in this tablet may include a tabletcontaining all dibasic sodium phosphate or all sodium bicarbonate orother buffers from the Essential Buffers list. The amount of EffectiveBuffer Capacity per tablet may range from as little as about 4 mEq to asmuch as about 30 mEq.

[0548] Additional tablet disintegrants such as croscarmelose sodium,pregelatinized starch, or providone, and tablet binders such as tapioca,gelatin, or PVP may be added. Further, a film coating may be placed onthe tablet to reduce the penetration of light and improve ease ofswallowing. Formulation 17: One Phase Omeprazole 20 mg Tablet Omeprazolehas a pKa of 3.9; thus, the Essential pH = 3.9 + 0.7 ≧ 4.6 Examples ofbuffers that are soluble at pH 4.6 or greater include, but are notlimited to, sodium bicarbonate, sodium carbonate, disodium hydrogenphosphate (dibasic sodium phosphate), and dipotassium phosphate. Enoughpowder for 11 tablets is weighed out: Proton pump inhibitor: Omeprazolepowder USP  220 mg Primary Essential Buffer(s): Sodium bicarbonate USP6500 mg Magnesium oxide powder 1650 mg Croscarmelose sodium  300 mg

[0549] The resultant powder is thoroughly mixed. Then 788 mg of thehomogeneous mixture is poured into a tablet reservoir (½ inch diameter)and pressed through a full motion of the press as is known in the art.The resultant tablet contains: Omeprazole USP   20 mg Sodium bicarbonateUSP   590 mg Magnesium oxide   150 mg Croscarmelose sodium 27.27 mg

[0550] The tablet contains 7 mEq sodium bicarbonate and 3.75 mEqmagnesium oxide. The amount of Effective Buffer Capacity may range fromas little as about 4 mEq to as much as about 30 mEq. The tabletexcipients, tablet binders, and film coating of Formulation 16 may alsobe added. Formulation 18: One Phase Omeprazole 40 mg Tablet Enoughpowder for 11 tablets is weighed out: Proton pump inhibitor: Omeprazolepowder USP  440 mg Primary Essential Buffer(s): Sodium bicarbonate USP6500 mg Magnesium oxide 1650 mg Pregelatinized starch  500 mg

[0551] The resultant powder is thoroughly mixed. Then 826 mg of thehomogeneous mixture is poured into a tablet reservoir (½ inch diameter)and pressed through a full motion of the press as is known in the art.The resultant tablet contains: Omeprazole USP 40 mg Sodium bicarbonateUSP 590 mg Magnesium oxide 150 mg Pregelatinized starch 45.45 mg

[0552] The tablet contains 7 mEq sodium bicarbonate and 3.75 mEqmagnesium oxide. The amount of Effective Buffer Capacity may range fromas little as 4 mEq to as much as 30 mEq. The tablet excipients, tabletbinders, and film coating of Formulation 16 may also be added.

[0553] Esomeprazole magnesium or other proton pump inhibiting agentswhich are of low solubility (such as the base forms) may be used inplace of omeprazole or lansoprazole in the above formulations. Thetablet excipients, tablet binders, and film coatings of Formulation 16may also be added. In addition, powders of any of the formulationsdisclosed herein may be manufactured by thoroughly mixing the powders aswhen making tablets and omitting the pressing of the tablets. The powderis packaged in a suitable container protecting the formulation from airmoisture and light such as a foil pack or sachet. When added to a volumeof water (e.g. 3 to 20 mL) the formulation may be taken orally oradministered down a feeding or NG tube, etc. Flavoring agents such asare outlined in the above formulations may be used, for example, carmelflavor 0.1% w/w. For bitter tasting proton pump inhibiting agents suchas pantoprazole, omeprazole, esomperazole and rabeprazole, the use ofthaumatin in a quantity of 5 to 10 ppm may be useful in masking thebitterness. Sweeteners such as sucrose or aspartame may also beemployed. Tablet disintegrants such as croscarmelose sodium and glidantssuch as magnesium stearate may additionally be used. Formulation 19:Omeprazole Powder Formulations (single dose) Proton pump inhibitor:Omeprazole powder USP 20 mg or 40 mg (or esomeprazole magnesium).Primary Essential Buffer(s): Sodium bicarbonate USP powder (60 micron)1000 mg Magnesium oxide USP powder 500 mg Optional Secondary EssentialBuffer(s): Tribasic sodium phosphate 200 mg* Other ingredients: Dextrose60 mg Xanthan gum (Rhodigel ultra fine) 15 mg Thaumatin (Flavorenhancer) 5 to 10 ppm

[0554] Thoroughly blend the powder, reconstitute all of the powder with5 ml to 20 ml distilled water and administer the suspension enterally tothe patient. Formulation 20: Unflavored Omeprazole Powder (single dose)Omeprazole powder USP 20 mg or 40 mg Sodium bicarbonate USP 1500 mgParietal cell activator: Calcium chloride 200 mg Other ingredients:Dextrose 60 mg Xanthan gum (Rhodigel ulta fine) 15 mg Thaumatin (Flavorenhancer) 5 to 10 ppm

[0555] Thoroughly blend the powder. Reconstitute all of the powder with5 mL to 20 mL distilled water and administer the suspension enterally tothe patient. Formulation 21: Flavored Omeprazole Powder (single dose)Omeprazole powder USP 20 mg Dibasic sodium Phosphate duohydrate 2000 mgSodium bicarbonate USP 840 mg to 1680mg Sucrose 2.6 g Maltodextrin 200mg Cocoa processed with alkali* 180 mg Corn syrup solids 600 mg Xanthangum 15 mg Aspartame 15 mg Thaumatin 2 mg Soy lecithin 10 mg

[0556] Thoroughly blend the powder. Reconstitute all of the powder with10 mL to 20 mL distilled water at the time of use. Formulation 22:Unflavored Lansoprazole Powder (single dose) Lansoprazole powder USP  15mg or 30 mg Sodium bicarbonate USP 400 mg to 1500 mg

[0557] Thoroughly blend the powder. Reconstitute all of the powder with5 mL to 20 mL distilled water at the time of use. Formulation 23:Flavored Lansoprazole Powder (single dose) Proton pump inhibitor:Lansoprazole powder USP 30 mg Primary Essential Buffer(s): DibasicSodium Phosphate USP or 1500 mg Sodium bicarbonate USP Sucrose 26 gMaltodextrin 2 g Cocoa processed with alkali* 18 mg Corn syrup solids600 mg Soy lecithin 80 mg

[0558] Thoroughly blend the powder. Reconstitute all of the powder with5 mL to 20 mL distilled water at the time of use. Formulation 24:Unflavored Rabeprazole Powder (single dose) Proton pump inhibitor:Rabeprazole sodium powder USP 20 mg Primary Essential Buffer(s):Disodium phosphate duohydrate USP 2000 mg Optional Secondary EssentialBuffer(s) Tribasic sodium phosphate 100 mg

[0559] Thoroughly blend the powder and reconstitute with distilled waterprior to administration. Optionally, thickeners and flavoring agents maybe added as stated throughout this application. The anticipated volumefor this powder would be 20 mL per dose. This formulation is designed toenhance stability of rabeprazole through the use of the common ioneffect whereby sodium causes a “salting out” of rabeprazole sodium. Thiscauses the rabeprazole sodium to remain insoluble thereby increasing itsstability. Formulation 25: Unflavored Rabeprazole Powder (single dose)Proton pump inhibitor: Rabeprazole sodium powder USP 20 mg PrimaryEssential Buffer(s): Sodium bicarbonate USP 1200 mg Secondary EssentialBuffer(s): Trisodium phosphate USP 300 mg Optional Secondary EssentialBuffer(s): Sodium hydroxide or Tribasic potassium may be added in higheror lower amounts to adjust pH for desired stability and additive antacidor buffering capacity.

[0560] Thoroughly blend the powder and reconstitute with 15 mL distilledwater at the time of use.

[0561] Alternatively, a two part product may be employed comprising onepart of about 5 to about 15 mL distilled water with a low concentrationof Secondary Essential Buffer (e.g. trisodium phosphate (100 mg) orsodium hydroxide (50 mg)) used to dissolve an enteric-coated tablet ofrabeprazole thereby producing a stable solution/suspension. This highlyalkaline suspension containing low neutralization capacity andrabeprazole sodium may then be added with a second part containing thePrimary Essential Buffer(s) having significant neutralization capacity.If desired other Secondary Essential Buffer(s) may be included with thePrimary Essential Buffers. This formulation is designed to enable theuse of the commercially available enteric-coated tablet of rabeprazoleas the source of the proton pump inhibitor. This tablet requiresdisintegration prior to use as a liquid formulation. Part 1 (the lowconcentration of Secondary Essential Buffer) produces rapid dissolutionof the delayed-release tablet as well as prolonged stability ofrabeprazole sodium in the liquid form. This enables the preparation tobe prepared prior to administration and simply added to the PrimaryEssential Buffer(s) (part 2) prior to use. Formulation 26: UnflavoredRabeprazole Powder (single dose) Proton pump inhibitor: Rabeprazolesodium powder USP 20 mg Primary Essential Buffer(s): Calcium lactate USP700 mg Calcium glycerophosphate 700 mg Secondary Essential Buffer(s):Calcium hydroxide USP 15 mg

[0562] Thoroughly blend the powder. Reconstitute the powder with aliquid part comprising 10 mL glycerol and 10 mL distilled water at thetime of use. Alternatively, the liquid for reconstitution may be onlywater (e.g. distilled) and contain some of the buffer. The liquid forreconstitution may be supplied as a buffered product (to pH 9-11) fordissolving rabeprazole sodium delayed-release tablets (if used as asource of rabeprazole sodium). Formulation 27: Unflavored EsomeprazolePowder (single dose) Proton pump inhibitor: Esomeprazole magnesiumpowder USP 20 mg Primary Essential Buffer(s): Calcium lactate USP 800 mgCalcium glycerophosphate 800 mg Secondary Essential Buffer(s): Calciumhydroxide USP 15 mg

[0563] Thoroughly blend the powder. Reconstitute the powder with aliquid part comprising of 10 mL distilled water at the time of use. Theliquid for reconstitution may be supplied as a buffered product (to pH8-11) for dissolving esomeprazole magnesium delayed release granules (ifused as a source of esomeprazole magnesium). Formulation 28: OmeprazoleTwo Part Tablet Two part tablets contain an outer buffer phase and innerbuffer/Proton pump inhibitor core. Enough for 6 tablets is weighed out.Inner Core: Proton pump inhibitor: Omeprazole powder USP  120 mg (oresomeprazole magnesium or omeprazole sodium). Primary EssentialBuffer(s): Sodium bicarbonate USP 1200 mg Outer Phase: Sodiumbicarbonate USP 3960 mg

[0564] Thoroughly blend the powders for the inner core, then weigh outapproximately 220 mg of the resultant blend and add to a die of ⅜″diameter. The powder mixture is then formulated into small tablets byconventional pharmaceutical procedures. Repeat for five additionaltablets, then set these small inner tablets aside.

[0565] The outside layer surrounding the proton pump inhibitor tabletserves as a pH-buffering zone. Enough sodium bicarbonate for 6 tabletsis weighed out with approximately 280 mg per tablet for a total of 1680mg sodium bicarbonate USP. Then weigh out approximately 280 mg of theresultant blend and add to a die of ½″ diameter. Press through a fullmotion to compact the powder into a tablet. Place the tablet back intothe ½ inch die and then place the smaller ⅜″ tablet (inner tablet) ontop of the ½″ tablet and center it. Add approximately 380 mg sodiumbicarbonate to the die on top of the ½″ tablet and the ⅜″ tablet. Pressthrough a full motion to compact the materials into one tablet. Theapproximate weight of each tablet is 815 mg to 890 mg containing 20 mgomeprazole. Binders such as tapioca or PVP and disintigrants such aspregelatinized starch may be added. The outer lay may also comprisepharmaceutically acceptable tablet exipients. Optional coatings can alsobe employed, for example, light film coatings and coatings to repelultraviolet light as is known in the art.

[0566] Magnesium oxide or magnesium hydroxide may be substituted for thesodium bicarbonate outer phase. Enough magnesium oxide for 6 tablets isweighed out with approximately 280 mg per tablet for a total of 1680 mgmagnesium oxide USP. Then weigh out approximately 280 mg of theresultant blend and add to a die of ½″ diameter. Press through a fullmotion to compact the powder into a tablet. Place the tablet back intothe ½ inch die and then place the smaller ⅜″ tablet (inner tablet) ontop of the ½″ tablet and center it. Add approximately 380 mg magnesiumoxide to the die on top of the ½″ tablet and the ⅜″ tablet. Pressthrough a full motion to compact the materials into one tablet. Theapproximate weight of each tablet is 815 mg to 890 mg containing 20 mgomeprazole. Binders such as tapioca or PVP and disintigrants such aspregelatinized starch, croscarmelose sodium or microcrystallinecellulose (MCC) and colloidal silicone dioxide (CSD) may be added. Theouter layer may also comprise pharmaceutically acceptable tabletexipients. Optional coatings can also be employed, for example, lightfilm coatings and coatings to repel ultraviolet light as is known in theart.

[0567] The outer phase can alternatively comprise a combination ofsodium bicarbonate and magnesium oxide. Formulation 29: Lansoprazole TwoPart Tablet Enough for 6 tablets is weighed out. Inner Core: Proton pumpinhibitor: Lansoprazole powder USP  180 mg Primary Essential Buffer:Sodium bicarbonate USP 1200 mg Outer Phase: Sodium bicarbonate USP 3960mg

[0568] Thoroughly blend the powders of the inner core, then weigh outapproximately 230 mg of the resultant blend and add to a die of ⅜″diameter. The inner and outer tablets are then formed as described inFormulation 28. The approximate weight of each tablet is 825 mg to 900mg. Binders such as tapioca or PVP and disintigrants such aspregelatinized starch may be added. Formulation 30: Pantoprazole TwoPart Tablet Enough for 6 tablets is weighed out. Inner Core: Proton pumpinhibitor: Pantoprazole powder USP  240 mg (or pantoprazole sodium)Primary Essential Buffer: Sodium bicarbonate USP 1200 mg Outer Phase:Sodium bicarbonate USP 3960 mg

[0569] Thoroughly blend the powders for the inner core, then weigh outapproximately 220 mg of the resultant blend and add to a die of ⅜″diameter. The inner and outer tablets are then formed as described inFormulation 28. The approximate weight of each tablet is 835 mg to 910mg. Binders such as tapioca or PVP and disintigrants such aspregelatinized starch or croscarmelose sodium may be added. Formulation31: Omeprazole or esomeprazole two part tablet. Enough for 6 tablets isweighed out. Inner Core: Proton pump inhibitor: Omeprazole powder USP(or esomeprazole or  120 mg omeprazole sodium). Primary EssentialBuffer: Sodium bicarbonate 1200 mg Outer Phase: Sodium bicarbonate 3960mg

[0570] Thoroughly blend the powders of the inner core, then weigh outapproximately 220 mg of the resultant blend and add to a die of ⅜″diameter. The inner and outer tablets are then formed as described inFormulation 28. The approximate weight of each tablet is 815 mg to 890mg. Binders such as tapioca or PVP and disintigrants have been mentionedand may be added. Secondary Essential Buffers such as trisodiumphosphate, tripotassium phosphate or sodium carbonate or others may beadded to enhance neutralization capacity. Formulation 32: LansoprazoleTwo part tablet Enough for 6 tablets is weighed out. Inner Core: Protonpump inhibitor: Lansoprazole powder USP  180 mg Primary EssentialBuffer: Sodium bicarbonate 1200 mg Outer Phase: Sodium bicarbonate 3960mg

[0571] Thoroughly blend the powder of the inner core, then weigh outapproximately 230 mg of the resultant blend and add to a die of ⅜″diameter. The inner and outer tablets are then formed as described inFormulation 28. The approximate weight of each tablet is 825 mg to 900mg. Binders such as tapioca or PVP and disintigrants have been mentionedand may be added. Secondary Essential Buffers such as trisodiumphosphate, tripotassium phosphate or sodium carbonate or others may beadded to enhance neutralization capacity. Formulation 33: PantoprazoleTwo part tablet Enough for 6 tablets is weighed out. Inner Core: Protonpump inhibitor: Pantoprazole sodium powder USP  240 mg Primary EssentialBuffer: Sodium bicarbonate 1200 mg Outer Phase: Sodium bicarbonate 3960mg

[0572] Thoroughly blend the powders of the inner core, then weigh outapproximately 220 mg of the resultant blend and add to a die of ⅜″diameter. The inner and outer tablets are then formed as described inFormulation 28. The approximate weight of each tablet is 835 mg to 910mg. Binders such as tapioca or PVP and disintegrants may also be added.Secondary Essential Buffers, such as trisodium phosphate, tripotassiumphosphate, sodium carbonate or others, may be added to enhanceneutralization capacity. Formulation 34: Omeprazole 20 mg Two-PartTablet Inner Core: Proton pump inhibitor: Omeprazole enteric coatedgranules (base, or  20 mg sodium salt or esomeprazole sodium ormagnesium) Outer Phase: Sodium bicarbonate powder USP 1000 mg

[0573] The inner core is created as is known in the art such that theenteric coatings on the granules remain substantially intact. The outerphase is bound to the inner core as described in Formulation 28. Othervariations of this tablet include a uniform enteric coating surroundingthe proton pump inhibitor of the inner core instead of separate entericcoated granules. Formulation 35: Lansoprazole 30 mg Two-Part TabletInner Core: Proton pump inhibitor: Lansoprazole enteric coated granules 30 mg Outer Phase: Sodium bicarbonate powder USP 1000 mg

[0574] This two-part tablet is formulated as per Formulation 34.Formulation 36: Rabeprazole 20 mg Two-Part Tablet Inner Core: Protonpump inhibitor: Rabeprazole enteric coated granules  20 mg Outer Phase:Sodium bicarbonate powder USP 1000 mg

[0575] This two-part tablet is formulated as per Formulation 34.Formulation 37: Omeprazole Two Part Tablet Enough for 6 tablets isweighed out Inner Core: Omeprazole  120 mg Sodium bicarbonate power USP1200 mg Outer Phase: Magnesium oxide 1500 mg Optional - calciumcarbonate 3000 mg

[0576] The omeprazole and sodium bicarbonate of the inner core arehomogeneously mixed and formed as in Formulation 28. The outer phase iscombined with the inner core as in Formulation 28. Formulation 38:Combination Antacid and Enteric Coated Dosage Form Omeprazole enteric 20 mg (or an equivalent coated granules or dose of another entericcoated tablet proton pump inhibitor) Calcium carbonate 1000 mg

[0577] The above components are combined with care exerted to ensurethat the enteric coating is not crushed or otherwise compromised. Theresulting combination is then formed into compressed tablets or placedin capsules as is known in the pharmaceutical art. If enteric coatedgranules are employed, they are generally, but not required, dispersedthroughout the tablet or capsule. If an enteric coated tablet isalternatively utilized, it forms a central core, which is uniformlysurrounded by the calcium carbonate in either a compressed tablet or ina larger capsule. In another embodiment, a capsule containing entericcoated granules of proton pump inhibitor can be placed within a largercapsule containing the calcium carbonate.

[0578] It should be noted that other buffering agents can be utilized inlieu of or in combination with calcium carbonate. The buffer(s) employedis present in an amount of at least about 5 mEq per dose of thecomposition with the preferred range been 7.5 to 15 mEq. For example,sodium bicarbonate may be preferred over calcium carbonate and otherantacids (such as magnesium or aluminum salts) because in many cases,sodium bicarbonate more quickly lowers gastric pH. Formulation 39:Combination Rapid Release and Delayed Released Proton Pump Inhibitor andAntacid Inner core: Omeprazole enteric 10 or 20 mg (or an equivalentcoated granules or dose of another enteric coated tablet proton pumpinhibitor) Outer phase: Omeprazole powder 10 or 20 mg (or equivalentdose of another proton pump inhibitor) Calcium Carbonate 1000 mg powder

[0579] The constituents of the outer phase are uniformly mixed. Theinner core is created as is known in the art such that the entericcoatings on the granules or tablet remain substantially intact. Theouter phase is bound to the inner core as described herein and as knownin the art.

[0580] Formulation 40: Soft Chewable Proton Pump Inhibitor—Buffer DosageForm

[0581] Omeprazole 10 or 20 mg (or an equivalent dose of another protonpump inhibitor) is combined with the ingredients of a soft chewableantacid tablet (e.g., Viactiv®), which comprises calcium carbonate 500or 1000 mg, corn syrup, sugar, chocolate non fat milk, cocoa butter,salt, soy lecithin, glyceryl monostearate, flavoring (e.g., caramel),carrageenan, and sodium phosphate. Vitamins D3 and/or K1 can also beadded. The finished chew tablets are administered to patients once tothrice daily for gastric acid related disorders.

[0582] For all formulations herein, multiple doses may be proportionallycompounded as is known in the art.

[0583] The invention has been described in an illustrative manner, andit is to be understood the terminology used is intended to be in thenature of description rather than of limitation. All patents and otherreferences cited herein are incorporated herein by reference in theirentirety. Obviously, many modifications, equivalents, and variations ofthe present invention are possible in light of the above teachings.Therefore, it is to be understood that within the scope of the appendedclaims, the invention may be practiced other than as specificallydescribed.

I claim:
 1. A method of increasing absorption of a proton pumpinhibiting agent into blood serum of a subject, comprising: providing asolid pharmaceutical composition for administration to the subject, thecomposition comprising the proton pump inhibiting agent and a bufferingagent; and administering the pharmaceutical composition to the subject'sstomach whereby the composition contacts gastric fluid of the stomachand increases the absorption of the proton pump inhibiting agent intothe blood serum in an amount greater than the absorption of the protonpump inhibiting agent in the absence of the buffering agent; wherein thebuffering agent is in an amount sufficient to increase gastric fluid pHof the stomach to a pH that inhibits acid degradation of the proton pumpinhibiting agent in the gastric fluid so as to provide a measurableserum concentration upon pharmacokinetic testing.
 2. The method of claim1, wherein the composition is administered in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 0.15 μg/ml within about 15 minutes after ingestion ofthe composition.
 3. The method of claim 1, wherein the composition isadministered in an amount to achieve a measurable serum concentration ofthe proton pump inhibiting agent greater than about 0.15 μg/ml fromabout 15 minutes to about 1 hour after ingestion of the composition. 4.The method of claim 1, wherein the composition is administered in anamount to achieve a measurable serum concentration of the proton pumpinhibiting agent greater than about 0.15 μg/ml from about 15 minutes toabout 1.5 hours after ingestion of the composition.
 5. The method ofclaim 1, wherein the composition is administered in an amount to achievea measurable serum concentration of the proton pump inhibiting agentgreater than about 0.1 μg/ml within about 15 minutes after ingestion ofthe composition.
 6. The method of claim 1, wherein the composition isadministered in an amount to achieve a measurable serum concentration ofthe proton pump inhibiting agent greater than about 0.1 μg/ml from about15 minutes to about 1.5 hours after ingestion of the composition.
 7. Themethod of claim 1, wherein the composition is administered via a routeselected from the group consisting of oral, nasogastric, and stomachtube.
 8. The method of claim 1, wherein the pharmaceutical compositionis in a form selected from the group consisting of a tablet, capsule,powder, suspension tablet, effervescent tablet or capsule, granules, anda liquid created by mixing any of the foregoing with an aqueous medium.9. The method of claim 1, wherein the proton pump inhibiting agent isenteric coated.
 10. The method of claim 1, wherein the amount of theproton pump inhibiting agent absorbed into the blood serum istherapeutically effective in treating an acid related gastrointestinalcondition selected from the group consisting of duodenal ulcer disease,gastric ulcer disease, gastroesophageal reflux disease, erosiveesophagitis, poorly responsive symptomatic gastroesophageal refluxdisease, pathological gastrointestinal hypersecretory disease, ZollingerEllison Syndrome, and acid dyspepsia.
 11. The method of claim 1, whereinthe proton pump inhibiting agent is selected from the group consistingof omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole,pariprazole, and leminoprazole, or an enantiomer, isomer, derivative,free base, or salt thereof.
 12. The method of claim 1, wherein theamount of the proton pump inhibiting agent is about 5 mg to about 300mg.
 13. The method of claim 1, wherein the amount of the proton pumpinhibiting agent is about 10 mg to about 100 mg.
 14. The method of claim1, wherein the amount of the proton pump inhibiting agent is about 15mg.
 15. The method of claim 1, wherein the amount of the proton pumpinhibiting agent is about 20 mg.
 16. The method of claim 1, wherein theamount of the proton pump inhibiting agent is about 40 mg.
 17. Themethod of claim 1, wherein the amount of the buffering agent is about0.1 mEq to about 2.5 mEq per mg of proton pump inhibiting agent.
 18. Themethod of claim 1, wherein the amount of the buffering agent is about 10mEq to about 70 mEq.
 19. The method of claim 1, wherein the amount ofthe buffering agent is at least 10 mEq.
 20. The method of claim 1,wherein the amount of the buffering agent is about 20 mEq to about 40mEq.
 21. The method of claim 1, wherein the buffering agent comprises acombination of calcium carbonate and sodium bicarbonate.
 22. The methodof claim 1, wherein the buffering agent comprises a bicarbonate salt ofa Group IA metal.
 23. The method of claim 1, wherein the buffering agentcomprises at least one of magnesium hydroxide, magnesium lactate,magnesium gluconate, magnesium oxide, magnesium carbonate, or magnesiumsilicate.
 24. The method of claim 1, wherein the buffering agentcomprises at least one of calcium acetate, calcium glycerophosphate,calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate,calcium bicarbonate, calcium gluconate, or other calcium salts.
 25. Themethod of claim 1, wherein the buffering agent comprises sodiumbicarbonate.
 26. The method of claim 25, wherein the sodium bicarbonateis in an amount from about 250 mg to about 4000 mg.
 27. The method ofclaim 25, wherein the sodium bicarbonate is in an amount from about 1000mg to about 1680 mg
 28. The method of claim 25, wherein the sodiumbicarbonate is in an amount of at least about 800 mg.
 29. The method ofclaim 1, wherein the buffering agent comprises calcium carbonate. 30.The method of claim 29, wherein the calcium carbonate is in an amountfrom about 250 mg to about 4000 mg.
 31. The method of claim 29, whereinthe calcium carbonate is in an amount from about 500 mg to about 1000mg.
 32. The method of claim 29, wherein the calcium carbonate is in anamount of at least about 800 mg.
 33. The method of claim 1, wherein thecomposition is in a dosage form selected from the group consisting of atablet, powder, suspension tablet, chewable tablet, capsule,effervescent powder, effervescent tablet, pellet, and granule.
 34. Themethod of claim 1, wherein the composition further comprises adisintegrant, flow aid, lubricant, adjuvant, excipient, colorant,diluent, moistening agent, preservative, or a pharmaceuticallycompatible carrier.
 35. The method of claim 1, wherein the compositionfurther comprises a flavoring agent comprising aspartame, chocolate,root beer, peppermint, spearmint, or watermelon, and combinations of anyof the foregoing.
 36. The method of claim 1, wherein the composition isadministered once or twice a day.
 37. A method of treating an acidrelated gastrointestinal disorder in a subject in need thereof,comprising: orally administering to the subject a solid pharmaceuticalcomposition comprising a proton pump inhibiting agent and a bufferingagent; wherein the buffering agent is in an amount sufficient toincrease stomach content pH to a pH that inhibits acid degradation ofthe proton pump inhibiting agent in the stomach and to allow absorptionof the proton pump inhibiting agent into blood serum of the subject inan amount greater than the absorption of the proton pump inhibitingagent in the absence of the buffering agent; and wherein the amount ofproton pump inhibiting agent absorbed into the blood serum istherapeutically effective in treating the disorder.
 38. The method ofclaim 37, wherein the composition is administered in an amount toachieve a measurable serum concentration of the proton pump inhibitingagent greater than about 0.15 μg/ml within about 15 minutes afteradministration of the composition.
 39. The method of claim 37, whereinthe composition is administered in an amount to achieve a measurableserum concentration of the proton pump inhibiting agent greater thanabout 0.15 μg/ml from about 15 minutes to about 1 hour afteradministration of the composition.
 40. The method of claim 37, whereinthe composition is administered in an amount to achieve a measurableserum concentration of the proton pump inhibiting agent greater thanabout 0.15 μg/ml from about 15 minutes to about 1.5 hours afteradministration of the composition.
 41. The method of claim 37, whereinthe composition is administered in an amount to achieve a measurableserum concentration of the proton pump inhibiting agent greater thanabout 0.1 μg/ml within about 15 minutes after administration of thecomposition.
 42. The method of claim 37, wherein the composition isadministered in an amount to achieve a measurable serum concentration ofthe proton pump inhibiting agent greater than about 0.1 μg/ml from about15 minutes to about 1 hour after administration of the composition. 43.The method of claim 37, wherein the subject is fasting.
 44. The methodof claim 37, wherein the pharmaceutical composition is in a formselected from the group consisting of a tablet, capsule, powder,suspension tablet, effervescent tablet or capsule, granules, and aliquid created by mixing any of the foregoing with an aqueous medium.45. The method of claim 37, wherein the proton pump inhibiting agent isenteric coated.
 46. The method of claim 37, wherein the composition isadministered via a route selected from the group consisting of oral,nasogastric, and stomach tube.
 47. The method of claim 37, wherein theproton pump inhibiting agent is selected from the group consisting ofomeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole,pariprazole, and leminoprazole, or an enantiomer, isomer, derivative,free base, or salt thereof.
 48. The method of claim 37, wherein theamount of the proton pump inhibiting agent is in an amount of about 5 mgto about 300 mg.
 49. The method of claim 37, wherein the amount of theproton pump inhibiting agent is about 10 mg to about 100 mg.
 50. Themethod of claim 37, wherein the amount of the proton pump inhibitingagent is about 15 mg.
 51. The method of claim 37, wherein the amount ofthe proton pump inhibiting agent is about 20 mg.
 52. The method of claim37, wherein the amount of the proton pump inhibiting agent is about 40mg.
 53. The method of claim 37, wherein the buffering agent is about 0.1mEq to about 2.5 mEq per mg of proton pump inhibiting agent.
 54. Themethod of claim 37, wherein the amount of the buffering agent is about10 mEq to about 70 mEq.
 55. The method of claim 37, wherein the amountof the buffering agent is at least 10 mEq.
 56. The method of claim 37,wherein the amount of the buffering agent is about 20 mEq to about 40mEq.
 57. The method of claim 37, wherein the buffering agent comprises acombination of calcium carbonate and sodium bicarbonate.
 58. The methodof claim 37, wherein the buffering agent comprises a bicarbonate salt ofa Group IA metal.
 59. The method of claim 37, wherein the bufferingagent comprises at least one of magnesium hydroxide, magnesium lactate,magnesium gluconate, magnesium oxide, magnesium carbonate, or magnesiumsilicate.
 60. The method of claim 37, wherein the buffering agentcomprises at least one of calcium acetate, calcium glycerophosphate,calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate,calcium bicarbonate, calcium gluconate, or other calcium salts.
 61. Themethod of claim 37, wherein the buffering agent comprises sodiumbicarbonate.
 62. The method of claim 61, wherein the sodium bicarbonateis in an amount from about 250 mg to about 4000 mg.
 63. The method ofclaim 61, wherein the sodium bicarbonate is in an amount from about 1000mg to about 1680 mg
 64. The method of claim 61, wherein the sodiumbicarbonate is in an amount of at least about 800 mg.
 65. The method ofclaim 37, wherein the buffering agent comprises calcium carbonate. 66.The method of claim 65, wherein the calcium carbonate is in an amountfrom about 250 mg to about 4000 mg.
 67. The method of claim 65, whereinthe calcium carbonate is in an amount from about 500 mg to about 1000mg.
 68. The method of claim 65, wherein the calcium carbonate is in anamount of at least about 800 mg.
 69. The method of claim 37, wherein thecomposition is in a dosage form selected from the group consisting of atablet, powder, suspension tablet, chewable tablet, capsule,effervescent powder, effervescent tablet, pellet, and granule.
 70. Themethod of claim 37, wherein the composition further comprises adisintegrant, flow aid, lubricant, adjuvant, excipient, colorant,diluent, moistening agent, preservative, or a pharmaceuticallycompatible carrier.
 71. The method of claim 37, wherein the subject isan adult human.
 72. The method of claim 37, wherein the disorder isselected from the group consisting of duodenal ulcer disease, gastriculcer disease, gastroesophageal reflux disease, erosive esophagitis,poorly responsive symptomatic gastroesophageal reflux disease,pathological gastrointestinal hypersecretory disease, Zollinger EllisonSyndrome, and acid dyspepsia.
 73. The method of claim 37, wherein thecomposition further comprising a flavoring agent comprising aspartame,chocolate, root beer, peppermint, spearmint, or watermelon, andcombinations of any of the foregoing.
 74. The method of claim 37,wherein the composition is administered once or twice a day.
 75. Amethod of treating an acid related gastrointestinal disorder in asubject in need thereof, comprising: orally administering to the subjecta pharmaceutical composition in an oral dosage form for immediaterelease into an absorption pool having a highly acidic pH, thecomposition comprising a proton pump inhibiting agent and a bufferingagent; wherein the buffering agent is in an amount sufficient toincrease the pH of the absorption pool of the subject to a pH thatinhibits acid degradation of the proton pump inhibiting agent and toallow absorption of the proton pump inhibiting agent from the absorptionpool into blood serum of the subject in an amount greater than theabsorption of the proton pump inhibiting agent in the absence of thebuffering agent; and wherein the proton pump inhibiting agent is in anamount sufficient to achieve a measurable serum concentration in theblood serum of the subject after oral administration to the subject. 76.The method of claim 75, wherein the composition is administered in anamount to achieve a measurable serum concentration of the proton pumpinhibiting agent greater than about 0.15 μg/ml within about 15 minutesafter administration of the composition.
 77. The method of claim 75,wherein the composition is administered in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 0.15 μg/ml from about 15 minutes to about 1 hourafter administration of the composition.
 78. The method of claim 75,wherein the composition is administered in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 0.15 μg/ml from about 5 minutes to about 1.5 hoursafter administration of the composition.
 79. The method of claim 75,wherein the composition is administered in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 0.1 μg/ml within about 15 minutes afteradministration of the composition.
 80. The method of claim 75, whereinthe composition is administered in an amount to achieve a measurableserum concentration of the proton pump inhibiting agent greater thanabout 0.1 μg/ml from about 15 minutes to about 1.5 hours afteradministration of the composition.
 81. The method of claim 75, whereinthe subject is fasting.
 82. The method of claim 75, wherein thepharmaceutical composition is in a form selected from the groupconsisting of a tablet, capsule, powder, suspension tablet, effervescenttablet or capsule, granules, and a liquid created by mixing any of theforegoing with an aqueous medium.
 83. The method of claim 75, whereinthe proton pump inhibiting agent is enteric coated.
 84. The method ofclaim 75, wherein the composition is administered via a route selectedfrom the group consisting of oral, nasogastric, and stomach tube. 85.The method of claim 75, wherein the proton pump inhibiting agent isselected from the group consisting of omeprazole, lansoprazole,rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole,or an enantiomer, isomer, derivative, free base, or salt thereof. 86.The method of claim 75, wherein the amount of the proton pump inhibitingagent is in an amount of about 5 mg to about 300 mg.
 87. The method ofclaim 75, wherein the amount of the proton pump inhibiting agent isabout 10 mg to about 100 mg.
 88. The method of claim 75, wherein theamount of the proton pump inhibiting agent is about 15 mg.
 89. Themethod of claim 75, wherein the amount of the proton pump inhibitingagent is about 20 mg.
 90. The method of claim 75, wherein the amount ofthe proton pump inhibiting agent is about 40 mg.
 91. The method of claim75, wherein the buffering agent is about 0.1 mEq to about 2.5 mEq per mgof proton pump inhibiting agent.
 92. The method of claim 75, wherein theamount of the buffering agent is about 10 mEq to about 70 mEq. 93 Themethod of claim 75, wherein the amount of the buffering agent is atleast 10 mEq.
 94. The method of claim 75, wherein the amount of thebuffering agent is about 20 mEq to about 40 mEq.
 95. The method of claim75, wherein the buffering agent comprises a combination of calciumcarbonate and sodium bicarbonate.
 96. The method of claim 75, whereinthe buffering agent comprises a bicarbonate salt of a Group IA metal.97. The method of claim 75, wherein the buffering agent comprises atleast one of magnesium hydroxide, magnesium lactate, magnesiumgluconate, magnesium oxide, magnesium carbonate, or magnesium silicate.98. The method of claim 75, wherein the buffering agent comprises atleast one of calcium acetate, calcium glycerophosphate, calciumchloride, calcium hydroxide, calcium lactate, calcium carbonate, calciumbicarbonate, calcium gluconate, or other calcium salts.
 99. The methodof claim 75, wherein the buffering agent comprises sodium bicarbonate.100. The method of claim 99, wherein the sodium bicarbonate is in anamount from about 250 mg to about 4000 mg.
 101. The method of claim 99,wherein the sodium bicarbonate is in an amount from about 1000 mg toabout 1680 mg
 102. The method of claim 99, wherein the sodiumbicarbonate is in an amount of at least about 800 mg.
 103. The method ofclaim 75, wherein the buffering agent comprises calcium carbonate. 104.The method of claim 103, wherein the calcium carbonate is in an amountfrom about 250 mg to about 4000 mg.
 105. The method of claim 103,wherein the calcium carbonate is in an amount from about 500 mg to about1000 mg.
 106. The method of claim 103, wherein the calcium carbonate isin an amount of at least about 800 mg.
 107. The method of claim 75,wherein the composition is in a dosage form selected from the groupconsisting of a tablet, powder, suspension tablet, chewable tablet,capsule, effervescent powder, effervescent tablet, pellet, and granule.108. The method of claim 75, wherein the composition further comprises adisintegrant, flow aid, lubricant, adjuvant, excipient, colorant,diluent, moistening agent, preservative, or a pharmaceuticallycompatible carrier.
 109. The method of claim 75, wherein the subject isan adult human.
 110. The method of claim 75, wherein the disorder isselected from the group consisting of duodenal ulcer disease, gastriculcer disease, gastroesophageal reflux disease, erosive esophagitis,poorly responsive symptomatic gastroesophageal reflux disease,pathological gastrointestinal hypersecretory disease, Zollinger EllisonSyndrome, and acid dyspepsia.
 111. The method of claim 75, wherein thecomposition further comprising a flavoring agent comprising aspartame,chocolate, root beer, peppermint, spearmint, or watermelon, andcombinations of any of the foregoing.
 112. The method of claim 75,wherein the composition is administered once or twice a day.
 113. Amethod of making a pharmaceutical composition for oral administration toa subject, providing immediate release of a proton pump inhibiting agentand a buffering agent into an absorption pool having a highly acidic pH,comprising: admixing the proton pump inhibiting agent and the bufferingagent; wherein the buffering agent is in an amount sufficient toincrease the pH of the absorption pool of the subject to a pH thatinhibits acid degradation of the proton pump inhibiting agent and toallow absorption of the proton pump inhibiting agent from the absorptionpool into blood serum of the subject in an amount greater than theabsorption of the proton pump inhibiting agent in the absence of thebuffering agent; and wherein the proton pump inhibiting agent is in anamount sufficient to achieve a measurable serum concentration in theblood serum of the subject after oral administration to the subject.114. The method of claim 113, wherein the amount of buffering agentachieves a measurable serum concentration of the proton pump inhibitingagent greater than about 0.15 μg/ml within about 15 minutes afteradministration of the composition.
 115. The method of claim 113, whereinthe amount of buffering agent achieves a measurable serum concentrationof the proton pump inhibiting agent greater than about 0.15 μg/ml fromabout 15 minutes to about 1 hour after administration of thecomposition.
 116. The method of claim 113, wherein the amount ofbuffering agent achieves a measurable serum concentration of the protonpump inhibiting agent greater than about 0.15 μg/ml from about 15minutes to about 1.5 hours after administration of the composition. 117.The method of claim 113, wherein the amount of buffering agent achievesa measurable serum concentration of the proton pump inhibiting agentgreater than about 0.1 μg/ml within about 15 minutes afteradministration of the composition.
 118. The method of claim 113, whereinthe amount of buffering agent achieves a measurable serum concentrationof the proton pump inhibiting agent greater than about 0.1 μg/ml fromabout 15 minutes to about 1.5 hours after administration of thecomposition.
 119. The method of claim 113, wherein the composition isadministered via a route selected from the group consisting of oral,nasogastric, and stomach tube.
 120. The method of claim 113, wherein thepharmaceutical composition is in a form selected from the groupconsisting of a tablet, capsule, powder, suspension tablet, effervescenttablet or capsule, granules, and a liquid created by mixing any of theforegoing with an aqueous medium.
 121. The method of claim 113, whereinthe proton pump inhibiting agent is enteric coated.
 122. The method ofclaim 113, wherein the proton pump inhibiting agent is acid sensitive.123. The method of claim 113, wherein the proton pump inhibiting agentis selected from the group consisting of omeprazole, lansoprazole,rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole,or an enantiomer, isomer, derivative, free base, or salt thereof. 124.The method of claim 113, wherein the amount of the proton pumpinhibiting agent is about 5 mg to about 300 mg.
 125. The method of claim113, wherein the amount of the proton pump inhibiting agent is about 10mg to about 100 mg.
 126. The method of claim 113, wherein the amount ofthe proton pump inhibiting agent is about 15 mg.
 127. The method ofclaim 113, wherein the amount of the proton pump inhibiting agent isabout 20 mg.
 128. The method of claim 113, wherein the amount of theproton pump inhibiting agent is about 40 mg.
 129. The method of claim113, wherein the amount of the buffering agent is about 0.1 mEq to about2.5 mEq per mg of proton pump inhibiting agent.
 130. The method of claim113, wherein the amount of the buffering agent is about 10 mEq to about70 mEq.
 131. The method of claim 113, wherein the amount of thebuffering agent is at least 10 mEq.
 132. The method of claim 113,wherein the amount of the buffering agent is about 20 mEq to about 40mEq.
 133. The method of claim 113, wherein the buffering agent comprisesa combination of calcium carbonate and sodium bicarbonate.
 134. Themethod of claim 113, wherein the buffering agent comprises a bicarbonatesalt of a Group IA metal.
 135. The method of claim 113, wherein thebuffering agent comprises at least one of magnesium hydroxide, magnesiumlactate, magnesium gluconate, magnesium oxide, magnesium carbonate, ormagnesium silicate.
 136. The method of claim 113, wherein the bufferingagent comprises at least one of calcium acetate, calciumglycerophosphate, calcium chloride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, calcium gluconate, or othercalcium salts.
 137. The method of claim 113, wherein the buffering agentcomprises sodium bicarbonate.
 138. The method of claim 137, wherein thesodium bicarbonate is in an amount from about 250 mg to about 4000 mg.139. The method of claim 137, wherein the sodium bicarbonate is in anamount from about 1000 mg to about 1680 mg
 140. The method of claim 137,wherein the sodium bicarbonate is in an amount of at least about 800 mg.141. The method of claim 113, wherein the buffering agent comprisescalcium carbonate.
 142. The method of claim 141, wherein the calciumcarbonate is in an amount from about 250 mg to about 4000 mg.
 143. Themethod of claim 141, wherein the calcium carbonate is in an amount fromabout 500 mg to about 1000 mg.
 144. The method of claim 141, wherein thecalcium carbonate is in an amount of at least about 800 mg.
 145. Themethod of claim 113, wherein the composition is in a dosage formselected from the group consisting of a tablet, powder, suspensiontablet, chewable tablet, capsule, effervescent powder, effervescenttablet, pellet, and granule.
 146. The method of claim 113, wherein thecomposition further comprises a disintegrant, flow aid, lubricant,adjuvant, excipient, colorant, diluent, moistening agent, preservative,or a pharmaceutically compatible carrier.
 147. The method of claim 113,wherein the subject has an acid related gastrointestinal disorder. 148.The method of claim 147, wherein the disorder is selected from the groupconsisting of duodenal ulcer disease, gastric ulcer disease,gastroesophageal reflux disease, erosive esophagitis, poorly responsivesymptomatic gastroesophageal reflux disease, pathologicalgastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, andacid dyspepsia.
 149. The method of claim 113, wherein the compositionfurther comprising a flavoring agent comprising aspartame, chocolate,root beer, peppermint, spearmint, or watermelon, and combinations of anyof the foregoing.
 150. The method of claim 113, wherein the compositionis administered once or twice a day.